Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
National Human Genome Research Institute (NHGRI), (http://www.genome.gov)

Title: A Data Coordination Center for the Knockout Mouse Project (KOMP)

Announcement Type
New

Request For Applications (RFA) Number: RFA-HG-05-008

Catalog of Federal Domestic Assistance Number(s)
93.172

Key Dates
Release Date: September 8, 2005
Letters of Intent Receipt Date(s): October 20, 2005
Application Receipt Dates(s): November 22, 2005
Peer Review Date(s): January-March, 2006
Council Review Date(s): May 2006
Earliest Anticipated Start Date: July 1, 2006
Expiration Date: November 23, 2005

Applicant Information Meeting:
October 6, 2005, 2-4 p.m.
NIH main Campus, Bldg 50
1st Floor Conference Center
National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

  Section I. Funding Opportunity Description
   1. Research Objectives

  Section II. Award Information
   1. Mechanism(s) of Support
   2. Funds Available

  Section III. Eligibility Information
   1. Eligible Applicants
     A. Eligible Institutions
     B. Eligible Individuals
   2.Cost Sharing or Matching
   3. Other - Special Eligibility Criteria

  Section IV. Application and Submission Information
   1. Address to Request Application Information
   2. Content and Form of Application Submission
   3. Submission Dates and Times
     A. Receipt and Review and Anticipated Start Dates
       1. Letter of Intent
     B. Sending an Application to the NIH
     C. Application Processing
   4. Intergovernmental Review
   5. Funding Restrictions
   6. Other Submission Requirements

 Section V. Application Review Information
   1. Criteria
   2. Review and Selection Process
     A. Additional Review Criteria
     B. Additional Review Considerations
     C. Sharing Research Data
     D. Sharing Research Resources
   3. Anticipated Announcement and Award Dates

  Section VI. Award Administration Information
   1. Award Notices
   2. Administrative and National Policy Requirements
   3. Reporting

  Section VII. Agency Contact(s)
   1. Scientific/Research Contact(s)
   2. Peer Review Contact(s)
   3. Financial/ Grants Management Contact(s)

  Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement


Section I. Funding Opportunity Description

1. Research Objectives

The NIH plans to support the Knockout Mouse Project (KOMP) through a research network for production of a comprehensive resource of mouse mutants in which every gene in the mouse genome has been knocked out by a null mutation marked with a reporter system of high utility. Each component of the research network will be responsible for tracking the status of generating the mouse mutants assigned to it. The purpose of this RFA is to solicit applications to develop and implement a Data Coordination Center (DCC) to serve as a centralized resource to track the progress of the project and to deliver this information to the research network, NIH staff, and the public.

This RFA is being issued to further the value of the mouse as a powerful and important tool in the study of human disease. For many years, mouse mutants with phenotypes that mimic human traits have served as critical research tools in understanding the genetics underlying mammalian biology. The importance of the mouse as a model organism was indicated by the inclusion of a goal for the construction of genetic and physical maps of the mouse genome in the initial plan for the Human Genome Project (HGP). In fact, the HGP was actually able to accomplish significantly more than generating such maps of the mouse genome, and a high quality, finished sequence of the mouse genome (strain C57BL/6) will be completed by the end of 2005. Another major genomic resource for mouse research has been developed by the Mammalian Gene Collection (MGC) project (http://mgc.nci.nih.gov/), which as of July 2005 included 15,325 full-ORF (open reading frame) cDNA clones, representing 11,501 individual mouse genes.  The goal of the MGC mouse cDNA program is to produce, by 2007, at least one full-ORF cDNA clone for each of the ~18,000 currently well-defined mouse genes.

To complement the mouse genome sequence and full-length cDNA collection, a defined genetic resource that can be used to elucidate gene function is needed. To this end, the attendees at an international meeting convened in the fall of 2003 strongly supported the establishment of a focused, large-scale international effort to produce a publicly available, comprehensive collection of mouse knockout strains, i.e. a library of mice containing a null mutation in every gene in the mouse genome (Austin, C.P, et al . Nature 36, 921-924 (2004)). The meeting attendees also recommended a phased production approach, beginning with the construction of a resource of ES cells comprising a comprehensive collection of null, ideally conditional, alleles. This was to be followed by the construction of mice from the ES cells and then phenotyping the mice with an increasingly sophisticated set of tests: Tier 1, or basic phenotyping, was to be done centrally on nearly all of the mice created by the project; and Tier 2, microarray and transcriptome based phenotyping, was to be carried out on a subset of these mice. Subsequent specialized phenotyping and further in depth analyses on specific mice would then be supported by individual labs.

There has subsequently been a significant set of international efforts to further define and deliver the proposed resource. In March 2005, the NIH held a workshop to update the concept and assess the status of the field (http://www.genome.gov/15014549). At that meeting, information was presented about the number of existing mouse knockouts (primarily null mutations); this information was based on data taken from the Mouse Genome Database (data curated from the published scientific literature) maintained by the Mammalian Genome Informatics (MGI) at Jackson Laboratories, gene trap sequence data submitted to the data base of genome survey sequencing (dbGSS) at the National Center for Biotechnology Information (NCBI), and a new inventory of available, but unreported, knockout mice. In summary, mutations, primarily nulls, have been constructed in approximately 10,000 unique mouse genes by either gene-trap or targeted knockout methods; although the response to the inventory request on unpublished mouse knockouts was good, it was not complete, so it is almost certain that this number is an underestimate of the number of unique mouse genes that have already been knocked out. However, most of these are still unavailable to the scientific public, and so cannot be considered as available to the proposed effort until they are deposited in public repositories.

Several international groups have been funded, or have planned, for efforts to create conditional mouse knockouts. For example, the European Conditional Mouse Mutagenesis Program (EUCOMM) has received funding to generate 20,000 conditional mutations (12,000 conditional gene-trap mutations and 8,000 conditional targeted mutations) in ES cells, all in strain 129. A complementary project is being considered in Canada. However, it was noted at the NIH workshop that, to date, the high throughput construction of conditional null mutant mice from mutated ES cells has not been validated. Furthermore, there have been a few reports that the procedures used to manipulate the conditional mutations in mice can introduce genetic artifacts. Therefore, the NIH workshop endorsed the recommendation of the 2003 meeting that a comprehensive collection of null mutants is an important tool for dissecting mammalian gene function and would be a critical complement to the conditional mutant resource being constructed elsewhere. Additionally, the NIH workshop endorsed several other points: (1) the preference of researchers for a resource fully based on the C57BL/6 strain, if technology were available to do that; (2) given that nearly 10,000 of the approximately 20-25,000 genes in the mouse genome have been knocked out (made null), isolation of mutations in a minimum of 10,000 remaining mouse genes is needed to complete the current resource; (3) given that of the estimated 10,000 genes that have already been knocked out, only 3 to 4,000 are represented in existing knockout mice currently residing in research laboratories around the world, an effort to collect and preserve as many as possible of these existing mutants as embryos is of high priority. Through this RFA and two companion RFAs (RFA-DA-06-009 and RFA-HG-05-008) the NIH is now establishing a Knockout Mouse Project (KOMP) to address the goals identified by the international research community over the past two years.

KOMP will be composed of two resource components: 1) a repository to collect new KOMP-generated resources and for repatriation of existing mice from research laboratories, and 2) the DCC. In addition, two experimental efforts are planned: 1) one or more projects called for in RFA-HG-05-007, whose goal is to make maximum progress towards the goal of completing the set of mouse knockouts across the entire mouse genome the most widely use mouse strain, C57BL/6. The RFA calls for two approaches: a) to generate (preferably in C57BL/6) null mutations for the mouse genes for which there has not yet been a null mutation produced and/or b) to produce a nearly complete set of mouse null mutations in C57BL/6 ES cells or mouse embyos by transposon or gene trapping mutagenesis; and 2) a set of projects, called for in RFA-DA-06-009, to develop C57BL/6 ES cell lines for efficient generation and germline transmission of targeted mutations.  Each of the funded experimental projects is expected to have its own independent informatics resources to track progress and provide this information to the public. The purpose of the DCC is to collect all relevant information from the repatriation/repository effort and from the individual experimental projects so that other investigators and the public can gain access to the information at a single site.

At this time, the precise nature of the experimental approach(es) that will be taken by the knockout mutation generation effort has not been specified. As described in RFA-HG-05-007, to which potential applicants to this RFA are referred for more details, the NIH's long-term objective is to generate a collection of null mutants marked with a reporter of high utility in mouse strain C57BL/6 . At present, there are a range of technologies that can be considered for use in attaining or making significant progress toward this goal. These include gene targeting or gene trapping in ES cells derived from strain 129, development of the derivative 129 mice, and subsequent breeding of the mutations into strain C57BL/6; gene targeting or gene trapping directly in strain C57BL/6 mice or ES cells and development of the derivative C57BL/6 mice; and transposon mutagenesis in C57BL/6 mice. As it is likely that more than one of these approaches will be pursued during the initial phase of the KOMP, over the next few years, the KOMP is expected to generate: 1) a collection of knockout mutant mice consisting of repatriated mice and those generated through new efforts funded as a result of RFA-HG-05-007, and 2) a collection of mutant ES cells from strain C57BL/6 and perhaps from strain 129. Thus, there will be a variety of data types that the DCC will be expected to be able to collect and disseminate. Examples of such data types include, but are not limited to: (A) for gene targeting -- information about the genes that have been assigned to the project, when the effort to knock out each gene is scheduled to begin or actually did begin, the features and sequence of the targeting construct, data that confirm a knockout has been successfully made, information that the ES cell has been deposited in a public resource and its repository location, and that a mouse has been made from the mutant ES cell line and its repository location (for the small number that will be made under RFA-HG-05-007 in quality control efforts); (B) for transposon or gene-trap mutagenesis -- confirmatory data that a gene has been hit by a transposon or gene-trap vector, information that an ES cell or a mouse has been made, information that the ES cell or mouse embryo has been deposited in a public resource, and its repository location.

The purpose of this RFA is to solicit applications for a project to develop and implement the Data Coordination Center (DCC) component of the KOMP research network. The DCC will be expected to obtain data from each of the participating KOMP Research Network projects -- the repatriation/repository effort, the mutant ES cell or mouse production pipelines and, to a lesser extent, from the developmental efforts.  These data should include, but are not limited to, a variety of information types relating to the production status of mutants (from vector design through production of mutant ES cells or mutant mice), development of improved C57BL/6 ES cell lines, and the locations of ES cells or mice (from both repatriation and production efforts) in NIH-supported repositories.  The DCC will compile and track several lists of mouse genes – those that have been mutated and for which ES cells or mice are available to investigators, those that have entered into the mutation production pipeline and their status in the pipeline, and those that remain to be taken up by the pipeline. The DCC will establish systems that will allow the KOMP Research Network projects, NIH staff, advisors, and the public to have access to this information. 

The DCC should provide multiple mechanisms for delivering data about mouse knockout genes, including a simple web interface for standard queries and a genome browser view of the status of mouse genes targeted and generated by the KOMP and other projects. A method of freely downloading large datasets from the DCC should be included so that users can acquire and analyze all or large parts of the data. The application should include information on how efficient and unencumbered access to the DCC will be maintained. The efforts of the DCC should be focused on collecting, tracking and distributing relevant information for the KOMP project, and should not duplicate the informatics efforts of other projects funded to describe the characteristics or functions of mouse genes. However, it will be important for the information in the DCC to be accessible to other such projects. Thus, the applicant also should describe how information from the DCC will be transferred to other mouse informatics resources including, but not limited to, the UCSC Genome Browser, ENSEMBL, NCBI, and Mouse Genome Informatics.

The efforts of the DCC should not duplicate the informatics efforts of other, international projects for generating null or conditional null mice. However, it will also be important for the KOMP to have access to information from, and provide information to, these related efforts. Thus, the DCC will also serve the KOMP Research Network as a central information resource regarding other publicly available null and conditional mouse mutations by obtaining information from the several other projects around the world that have or will be established to generate gene traps and targeted null and conditional mutations in the mouse genome.  In sum, the DCC will provide links to all groups funded through the KOMP Research Network, mechanisms to export data to and receive data from other mouse informatics resources, and a public website through which all of this information will be made available.

The DCC funded by this RFA is expected to be a stable resource that will gather data from the KOMP research network projects and integrate those data with related data from other mouse knockout efforts. The data should be stored in the DCC using robust data management tools capable of handling all of the mouse knockout data. Where possible, the applicant should use existing software modules for the DCC, such as those produced by the Generic Model Organism Database project (http:\\www.gmod.org). The DCC is expected to be able to work with the other funded projects of KOMP to establish the exact types and formats of data that will be included in the DCC to allow it to track the progress of the KOMP efforts. As the identity of these projects will not be known at the time that the applications in response to this RFA are due, the applications should provide a plan that addresses the data from all of the potential approaches to the generation of knockout C57BL/6 mice and for interacting with all potential sources of such mice. In addition to information about KOMP itself, sources of information about other mouse knockout efforts should include the International Gene Trap Consortium (http://www.igtc.ca/), the EUCOMM and other large mouse knockout projects as identified during the March 2005 NIH workshop, the Mouse Genome Informatics group (http://www.informatics.jax.org/), and other projects that are funded to generate new mouse mutants. For all of the data in the DCC, the sources of the data should be identified and links back to these sources should be provided.

Management Plan. The application should describe the management plan for the proposed project and how it will support achievement of the proposed goals. The plan should also describe how the DCC will interact with the various components of KOMP. Coordination of the awardee's activities with the informatics efforts of other international efforts to produce mouse knockouts must be described.

Data and resource release. NIH strongly endorses rapid release of genomic data and materials as a general practice. NIH has also identified the goal of the KOMP as the production of a “community resource” as described in the proceedings of the Meeting on Sharing Data from Large-Scale Biological Research Projects (http://www.wellcome.ac.uk/doc_wtd003208.html). As such, all data in the DCC should be freely available without restrictions using the guidelines described in the above proceedings. Applicants should also be familiar with the NIH statements regarding intellectual property of resources developed with Federal funds (http://www.ott.nih.gov/policy/rt_guide_final.html). Responses to this RFA should propose specific and comprehensive plans for data release, as the quality of this plan will be an important criterion in the review of the application. Additionally, applicants are strongly encouraged to make their software easily available to the academic community. The application should address how software or technology improvements developed under this funding will be publicly released. An appropriate data and resource release plan will be made a condition of the award made as a result of this RFA.

In summary, applicants for awards under this RFA:

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the NIH U01 cooperative agreement award mechanism. Under the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award". Plans for continuation of this program beyond this current funding opportunity are not definite.

2. Funds Available

The participating IC(s) intends to commit approximately $2.5 million in new funds in response to this RFA.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of the award will also vary. Although the financial plans of the IC(s) provide support for this program, an award pursuant to this funding opportunity is contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.

2. Cost Sharing or Matching

Cost sharing is not required.

The most current Grants Policy Statement can be found at: http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#matching_or_cost_sharing.

3. Other-Special Eligibility Criteria

Applicants for this RFA must have a proven track record of establishing and maintaining databases containing data similar to that which will be generated by the KOMP Research Network. Documentation of this track record must be included.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact Grants Info, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a Dun and Bradstreet ( D&B ) Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

3. Submission Dates and Times
Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates

Letter of Intent Receipt Date: October 20, 2005
Application Receipt Date(s): November 22, 2005
Peer Review Date: January-March, 2006
Council Review Date: May, 2006
Earliest Anticipated Start Date: July 1, 2006

Applicant Information Meeting:
October 6, 2005, 2-4 p.m.
NIH main Campus, Bldg 50
1st Floor Conference Center
National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Peter Good, Ph.D.
Division of Extramural Research
National Human Genome Research Institute
5635 Fisher Lane
Suite 4076, MSC 9305
Bethesda, MD 20892-9305
Telephone: (301) 496-7531
FAX: (301) 480-2770
Email: goodp@mail.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Rudy Pozzatti, Ph.D.
Office of Scientific Review
National Human Genome Research Institute
5635 Fisher Lane
Suite 4076, MSC 9306
Bethesda, MD 20892-9306
Telephone: (301) 402-0838
FAX: (301) 435-1580
Email: pozzattr@exchange.nih.gov

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NHGRI. Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.

6. Other Submission Requirements
None

Plan for Sharing Research Data

All applications must include a plan for sharing research data. The NIH data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing.

The adequacy of the resources dissemination plans and any related data sharing plans will be considered by the reviewers in their evaluation of the scientific and technical merit of the applications, and will include such considerations in their assigned priority scores. Program staff of the funding organization will take the reviewers' recommendations into consideration when making recommendations about funding applications, and negotiation of a satisfactory dissemination plan may be required prior to making an award. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Sharing Research Resources

In general, NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131).

The reasonableness of the research materials sharing plan will be assessed by the reviewers, who will include this assessment in their determination of scientific merit or the priority score. In addition, the adequacy of the materials sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the materials sharing will subsequently be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information

1. Criteria

The following will be considered in making funding decisions:

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NHGRI in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? How is the balance of the component activities proposed consistent with the needs and opportunities presented by the DCC's potential user communities?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? How adequate are the plans to collect and maintain data? How adequate are the proposed plans for informing the scientific community about the resource?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

2.A. Additional Review Criteria:

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, applications received in response to RFA-HG-05-008 will also be reviewed with respect to the following:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and priority score:

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, a determination of whether the proposed protections are adequate will be made.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score will not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing plan.

The reasonableness of the data sharing plan will be assessed by the reviewers, who will include this assessment in their determination of scientific merit or the priority score. Data regarding the status of the pipeline, quality control, and availability of complete resources that are to be disseminated to the research community should be addressed in the data sharing plan. In addition, the adequacy of the data sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. The presence of a data sharing plan will be part of the terms and conditions of the award. NHGRI will be responsible for monitoring the data sharing policy. The effectiveness of the data sharing activities will be subsequently evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

2.D. Sharing Research Resources

NIH policy requires that grant award recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

Applicants are strongly encouraged to make their software easily available to the academic community. To preserve utility to the community, the software and database schema should be transferable to another individual or team in the event that the original investigators are unwilling or unable to continue development.

The adequacy of the resource sharing plan will be assessed by the reviewers as to whether or not it will achieve the goals of KOMP, namely whether the KOMP resources will be available to all researchers in the public and private sectors.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The reasonableness of the research materials sharing plan will be assessed by the reviewers, who will include this assessment in their determination of scientific merit or the priority score. In addition, the adequacy of the materials sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the materials sharing will subsequently be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates
Not applicable

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the Principal Investigator will receive a written critique called a Summary Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 14 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the notice of grant award. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator and appropriate institutional official at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the U01 cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The KOMP Research Network will involve four distinct activities (generation of the knockout mouse resource, further development of the C57BL/6 ES cell system, KOMP repositories and the data coordination center); funding of these activities will be solicited by a set of set of four RFAs (HG-05-008, the current RFA-HG-05-007; RFA-DA-06-009; and an as-yet unpublished RFA for the KOMP repatriation/repositories that will be published by NCRR). All components of the KOMP program will be funded by cooperative agreements and a single Steering Committee (section 2.A.3) and a single Panel of Scientific Consultants (section 2.A.4) will serve for all of the KOMP activities. The Terms and Conditions described below are specific for this RFA (HG-05-008), but have been coordinated and made consistent with those described in the other RFAs soliciting components of the KOMP Research Network.

2.A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator (P.I.) will have the primary responsibility for defining the details for the DCC within the guidelines of RFA HG-05-008 and for performing the scientific activities. The P.I. will agree to collaborate with the other members of the KOMP Research Network and to accept close coordination, cooperation, and participation of NIH staff and advisors in those aspects of scientific and technical management of the project as described under "NIH Responsibilities." The awardee will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

The P.I. of a DCC will:

2.A.2. NIH Responsibilities

NIH Project Scientists will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. For the KOMP Research Network, a Project Scientist will be appointed from each of the Institutes that is responsible for the participating cooperative agreements, that is, NHGRI (this RFA and RFA HG-05-007), NIDA (RFA DA-06-009) and NCRR (NIH-funded, KOMP repositories).

For RFA-HG-05-008 (this RFA), the NHGRI Project Scientist will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination. However, the role of the NHGRI Project Scientist will be to facilitate and not to direct the activities. It is anticipated that decisions in all collaborative activities will be reached by consensus of the KOMP Research Network.

The Project Scientist will:

An NHGRI Program Director will be responsible for the normal stewardship of this award; this same Program Director may, in addition, be substantially involved as the NIH Project Scientist, as described above.

2.A.3. Collaborative Responsibilities

The Steering Committee will serve as the main governing board of the KOMP Research Network. The Steering Committee membership will include the P.I. of each awarded cooperative agreement and the NIH Project Scientists for the components of the KOMP Research Network. Additional members may be added by action of the Steering Committee. Members of the KOMP Working Group may attend the Steering Committee meetings. Government employees outside of KOMP Working Group members may also attend, if their expertise is required for specific discussions.

The Steering Committee will:

2.A.4. Panel of Scientific Consultants

The Panel of Scientific Consultants (PSC) will be responsible for reviewing and evaluating the progress of the members of the KOMP Research Network toward meeting their individual and collective goals. The PSC will provide recommendations to the KOMP Working Group, the Directors of NHGRI, NIDA and NCRR, as well as the Directors of the all other participating institutes, about continued support of the components of the KOMP Research Network. The Panel will be composed of four to six senior scientists with relevant expertise who are not P.I.s of a cooperative agreement involved in the KOMP Research Network. The Panel of Scientific Consultants will be appointed by the Directors of NHGRI, NIDA, and NCRR, with concurrence from the Directors of all other participating Institutes. The membership of the Panel of Scientific Consultants may be enlarged permanently, or on an ad hoc basis, as needed.

The Panel of Scientific Consultants will meet at least once a year and 2 to 3 times per year by conference call. During part of this meeting, there will be a joint meeting with the Steering Committee to allow the PSC members to interact directly with the awardees. Annually, the PSC will make recommendations to the NIH regarding progress of the KOMP Research Network and present advice about changes, if any, which may be necessary in the KOMP Research Network program to the Directors of NHGRI, NIDA and NCRR and the Directors of the other participating institutes.

2.A.5. KOMP Working Group

The KOMP Working Group consists of program staff from the each of the NIH institutes supporting the KOMP. The purpose of the KOMP Working Group will be to disseminate information about the progress of the KOMP Research Network to the participating institutes and to provide a forum for the participating institutes to discuss issues related to KOMP. The KOMP Working Group members will report to the Director of their respective IC. The KOMP Working Group will be chaired by the NHGRI Project Scientist for the knockout mouse resource component of the KOMP.

2.A.6. Arbitration Process

Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between the award recipient and the NHGRI may be brought to arbitration. An Arbitration Panel will be composed of (i) a designee of the awardee, (ii) one NHGRI designee, and (iii) a third designee with relevant expertise who is chosen by the other two. The Arbitration Panel will help resolve both scientific and programmatic issues that develop during the course of work and that restrict progress. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with NIH regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16.

2.A.7. Yearly Milestones

The awardee will be asked to define a set of yearly milestones at the time of the award and to update these milestones annually at the anniversary date. These will be made a condition of the award. In accord with the procedures described above, NHGRI may withhold or reduce funds if the project that substantially fails to meet its milestones or to maintain the state of the art.

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement. Awardees will be required to submit periodic (at least every six months) progress reports in a standard format, as agreed upon by the Steering Committee and the Scientific Advisory Panel.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Peter Good, Ph.D.
Division of Extramural Research
National Human Genome Research Institute
5635 Fisher Lane
Suite 4076, MSC 9305
Bethesda, MD 20892-9305
Telephone: (301) 496-7531
FAX: (301) 480-2770
Email: goodp@mail.nih.gov

2. Peer Review Contacts:

Rudy Pozzatti, Ph.D.
Office of Scientific Review
National Human Genome Research Institute
5635 Fisher Lane
Suite 4076, MSC 9306
Bethesda, MD 20892-9306
Telephone: (301) 402-0838
FAX: (301) 435-1580
Email: pozzattr@exchange.nih.gov

3. Financial or Grants Management Contacts:

Cheryl Chick
Grants Administration Branch
National Human Genome Research Institute
5635 Fisher Lane
Suite 4076, MSC 9306
Bethesda, MD 20892-9306
Telephone: (301) 402-0733
FAX: (301) 402-1951
Email: chickc@mail.nih.gov

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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