MATHEMATICAL MODELS OF CYTOKINE/CHEMOKINE NETWORKS IN HIV ASSOCIATED 
LUNG DISEASE

Release Date:  December 6, 2001

RFA:  RFA-HL-02-009

National Heart, Lung, and Blood Institute (NHLBI)
 (http://www.nhlbi.nih.gov)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
 (http://www.nibib.nih.gov)

Letter of Intent Receipt Date:  March 12, 2002
Application Receipt Date:       April 12, 2002

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  MODULAR 
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN 
$250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN 
SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

PURPOSE

The objective of this Request for Applications (RFA) is to stimulate research 
on the development and validation of mathematical models of cytokine/chemokine 
networks involved in the pathogenesis of human immunodeficiency virus type 1 
(HIV-1)- associated lung disease.  This RFA encourages the use of 
computational biological methods to create mathematical models of 
cytokine/chemokine networks (e.g., using nonlinear mathematical techniques) 
and innovative collaborations between biomathematicians, clinical 
investigators, and bench scientists.  An important aspect of this program will 
be formation of collaborations to validate the mathematical models using 
biological experimentation systems.

Another important goal is to attract junior level mathematicians and 
quantitative biologists into this area of biological research. To facilitate 
their participation the Mentored Quantitative Research Career Development 
Award (K25) has been included as one of the mechanisms of support under this 
RFA.   

Among the disciplines and expertise that may be appropriate for this research 
program are mathematical modeling, bioinformatics, computer programming, 
biostatistics, pathogenesis of infections, immunology, lung cell biology, 
molecular biology, virology, bacteriology, mycology, genetics, infectious 
diseases, lung pathology, pulmonology, and veterinary medicine.

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  Request for Applications (RFA), 
"Mathematical Models of Cytokine/Chemokine Networks in HIV Associated Lung 
Disease," 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/.

ELIGIBILITY REQUIREMENTS

R01 applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  

Domestic institutions only, may submit applications for K25 awards.  In 
addition, for K25 applications, former principal investigators on NIH research 
project (R01), program project (P01), center grants, (P50, P60), FIRST Awards 
(R29), SBIR/STTR awards, sub-projects of program project or center grants, 
K01, K08 or K23 awards, or the equivalent are not eligible.  Former principal 
investigators of an NIH Small Grant (R03) or Exploratory/Developmental Grants 
(R21) remain eligible. A candidate for the Mentored Quantitative Research 
Career Development Award may not concurrently apply for any other PHS award 
that duplicates the provisions of this award nor have another application 
pending award.

Racial/ethnic minority individuals, women, and persons with disabilities are 
encouraged to apply as Principal Investigators.  All current policies and 
requirements that govern the research grant programs of the National 
Institutes of Health (NIH) will apply to grants awarded under this RFA.  
Awards under this RFA to foreign institutions will be made only for research 
of very unusual merit, need, and promise, and in accordance with PHS policy 
governing such awards.

MECHANISM OF SUPPORT

This RFA will use the NIH individual research project grant (R01) and the 
Mentored Quantitative Research Career Development Award (K25) mechanisms of 
support.  A description of the K25 award is available on the web at:  
http://grants.nih.gov/grants/guide/pa-files/PA-99-087.html.  Individuals may 
apply for either an R01 grant or a K25 award under this RFA, but cannot apply 
for both grants.  Each application submitted for this RFA must be a complete, 
independent entity and not depend on any other application submitted in 
response to this RFA.

Responsibility for the planning, direction, and execution of each of the 
proposed projects will be solely that of the respective applicant.  The total 
project period for an application submitted in response to this RFA may not 
exceed 5 years.  This RFA is a one-time solicitation.  Future unsolicited 
competing continuation applications will compete with all investigator-
initiated applications and be reviewed according to the customary peer review 
procedures.  The anticipated award date is September 30, 2002.  

Although multidisciplinary approaches are encouraged, it is not the intent of 
this RFA to solicit applications for large studies encompassing a variety of 
individual subprojects, i.e., program projects.  If collaborative arrangements 
through subcontracts with other institutions are planned, consult the program 
staff listed under INQUIRIES.

Biomedical investigators without prior R29 or R01 support are encouraged to 
apply for R01s under this RFA and to identify their status on the front of the 
grant application.  

Applicants from institutions that have a General Clinical Research Center 
(GCRC) funded by the NIH National Center for Research Resources may wish to 
identify the GCRC as a resource for conducting the proposed research.  If so, 
a letter of agreement from either the GCRC program director or principal 
investigator should be included with the application.  

FUNDS AVAILABLE

It is anticipated that for fiscal year 2002, approximately $3.0 million, total 
costs, will be committed by NHLBI and $250,000, total costs, will be committed 
by NIBIB, for this RFA.  Award of grants pursuant to this RFA is contingent 
upon receipt of such funds for this purpose.  It is anticipated that up to 8-
10 new R01 grants will be awarded under this program and up to 
2-4 new K25 grants will be awarded under this program.  The specific numbers 
to be funded will, however, depend on the merit and scope of the applications 
received and on the availability of funds.
  
Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.  The total project period for an 
application submitted in response to this RFA may not exceed five years.  This 
RFA is a one-time solicitation.  Future unsolicited competing continuation 
applications will compete with all investigator-initiated applications and be 
reviewed according to the customary peer review procedures. 

For this RFA, funds for R01s must be requested in $25,000 direct cost modules 
and a maximum of 12 modules ($300,000 direct costs) per year may be requested 
unless the investigators are working with non-human primate models in which 
case a maximum of 18 modules ($450,000 direct costs ) per year may be 
requested.  A feature of the modular grant concept is that no escalation is 
provided for future years, and all anticipated expenses for all years of the 
project must be included within the number of modules being requested.  Only 
limited budgetary information will be required and any budget adjustments made 
by the 
Initial Review Group will be in modules of $25,000.  

For the K25 grants funded under this RFA, funding is determined by the 
allowable costs designated for the K25 type of award, salary of up to $75,000 
per year plus fringe benefits and research development support of up to 
$40,000 per year for the following expenses:  (a) tuition, fees, and books 
related to career development; (b) research expenses, such as supplies, 
equipment and technical personnel; c) travel to research meetings or training; 
(d) research support services including personnel and computer time.  
Ancillary Personnel Support:  Salary for mentors, secretarial, and 
administrative assistance etc., is not allowed.   Facilities and 
Administrative costs will be reimbursed at 8 percent of modified total direct 
costs.  

RESEARCH OBJECTIVES

Background

The cytokine/chemokine environment in the lung influences the ability of HIV-1 
to infect, replicate and evolve in lung cells.  Once present in lung cells 
(mostly alveolar macrophages) HIV-1 profoundly changes their ability to 
produce and respond to inflammatory mediators, which alters local immune 
responses.  A better understanding of the complex and redundant 
chemokine/cytokine networks in the lung is needed to understand the 
pathogenesis of  HIV-1 in the lung, the pathogenesis of HIV-1-related lung 
infections due to other viruses, bacteria, and fungi, and changes brought 
about by the reconstitution of immunity during highly active antiretroviral 
therapy (HAART).  Mathematical models are likely to help in this endeavor.
  
Numerous cytokine studies have taught us that manipulating a single 
interaction in the context of complex networks can lead to unexpected and 
often undesirable results.  Nonlinear mathematical models of 
cytokine/chemokine systems may aid in understanding the consequences of 
manipulating particular system components.  Most current studies follow events 
over a period of weeks, but the most crucial changes may be occurring during 
the first few minutes.  One could attempt to model the timing of events 
associated with cytokine release and activity, cytokine concentrations and 
precursor cell populations, and  attempt to predict what type of responses 
might occur.  Mathematical models could be used to help generate and test new 
hypotheses.  They could help explore and test new approaches to drug and 
immunomodulatory therapy that minimize the harmful aspects of HIV infection 
and host responses to HIV-associated infections, such as  P. carinii pneumonia 
and tuberculosis.  

Mathematical models based on available knowledge of cytokine/chemokine 
networks may provide insight into interactions involving these mediators, 
other components of the immune system, and microbes. The mathematical models 
could  be used to compare and contrast existing controversies and extend 
intuition about biological processes.  Computational models would offer new 
approaches to elucidating these complex reaction series, generating 
hypotheses, and clarifying existing data and theories. Creating the models 
will require close collaborations between clinicians, bench  scientists and 
biomathematicians and when successful, as for example in the case of 
apparently chaotic cardiac arrhythmias, can be quite helpful in revealing 
underlying mechanisms and pathologies.  Models based on differential equations 
could include parameters of  key processes, for example, rate constants, 
sensitivity and uncertainty analyses, and bifurcations.  The models could 
easily be perturbed.  Once developed the models could allow ideas to be 
explored quickly and inexpensively.  Some limitations of using models are that 
answers derived from them are based on the original  assumptions and that 
validation of the models may be difficult to achieve.  Models for control 
strategies of TB epidemics and models to understand the dynamics of HIV 
infection including, production, turnover, half-life, and possible reservoirs 
of infection have been developed.  Modeling HIV changed concepts about viral 
growth and lead to the realization of the highly dynamic growth of the virus.

Mathematical models might be useful in examining specific issues related to 
the pathogenesis of HIV-1 in the lung, including the following examples.  
Virus load in the lung is low early in disease, but rises significantly during 
the later stages of disease.  There is also a significant increase in 
pulmonary lymphocytosis, mainly due to CD8 cells.  It is not known if CD8 
cells, which suppress HIV-1 in a non-specific manner, exert control over virus 
populations through chemokine production, and how this might balance with 
virus-enhancing cytokines.  Three chemokines (MIP-1a, MIP-1ß, and RANTES) are 
largely responsible for HIV-1 suppression, but inhibit only M-tropic strains. 
 These three chemokines are also ligands for the M-tropic cofactor CCR5. The 
chemokine ligand for CXCR-4 (SDF) blocks infection by T-tropic strains, but 
its role in regulation of virus replication is unknown. 

Objectives and Scope

The purpose of this RFA is to stimulate research on the development and 
validation of mathematical models of cytokine/chemokine networks involved in 
the pathogenesis of human immunodeficiency virus type 1 (HIV)-Associated Lung 
Disease.  In particular this program  encourages the use of computational 
biological methods to create mathematical models of cytokine/chemokine 
networks.  The use of nonlinear mathematical techniques is of particular 
interest. The formation of collaborations between biomathematicians, clinical 
investigators, and bench scientists to validate the mathematical models using 
biological experimentation systems are strongly encouraged.  Another important 
aspect of this program will be attracting junior level mathematicians and 
other quantitative scientists into this area of biological research.  To 
facilitate their participation the Mentored Quantitative Research Career 
Development Award (K25) has been included as one of the mechanisms of support 
under this RFA. 

Mathematical models are needed to improve our understanding of the basic 
mechanisms of HIV-1 disease in the lung and expedite development and testing 
of new hypotheses. Cytokine/chemokine networks are crucial in mediating HIV-1-
associated inflammatory reactions and infections in the lung, but they are 
extremely complex and redundant, making it very difficult to learn about the 
consequences of perturbations to any part of the system.  The 
cytokine/chemokine environment in the lung influences the ability of HIV to 
infect, replicate and evolve in lung cells.  HIV-1 profoundly changes the 
ability of lung cells to produce and respond to inflammatory mediators and 
alters local immune responses.  Better knowledge of  chemokine/cytokine 
networks in the lung is needed to understand HIV-1 induced lung injury, HIV-1-
related lung infections due to other viruses, bacteria, and fungi and changes 
brought about by the reconstitution of immunity during highly active 
antiretroviral therapy (HAART). 
 													
This RFA program is particularly relevant to African American and Hispanic 
minority populations who are disproportionately affected by the HIV-1 epidemic 
in comparison to the total 
population. 

In responding to this RFA expertise might be needed in the following areas: 
mathematical modeling, bioinformatics, computer programming, biostatistics, 
pathogenesis of infections, immunology, lung cell biology, molecular biology, 
virology, bacteriology, mycology, genetics, infectious diseases, lung 
pathology, pulmonology, epidemiology, and veterinary medicine.

This RFA is co-sponsored by NHLBI and NIBIB.  NHLBI is interested in 
encouraging research on using mathematical approaches to understand the role 
of cytokine/chemokine networks in the pathogenesis of HIV infection and HIV-1-
associated infections in the lung.   Whereas, NIBIB is particularly interested 
in using this RFA to encourage the training of young biomathematicians and 
bioengineers and is primarily interested in sponsoring mentored career 
development awards (K25) under this program.  Bringing young mathematicians 
and other quantitative scientists into this area of research is of great 
interest to both institutes and NHLBI may also sponsor mentored research under 
this program.

Some examples of areas of research that might be included under this RFA are 
as follows:

o  What determines whether pulmonary inflammation or immune incompetence 
predominates.  This likely involves both pro- and anti-inflammatory cytokine 
networks in the lung. 

o  CD4 is the principal receptor for HIV entry and infection of target cells, 
but chemokine receptors are required, in conjunction with CD4, for HIV entry 
and infection.  These molecules normally function to induce signals mediated 
by chemokines, which are a family of  protein cytokines.  T-tropic isolates 
utilize the chemokine receptor CXCR-4 as a cofactor for entry, M-tropic 
strains use CCR5.  Many other chemokine co-receptors are being discovered, but 
little is known about their function and distribution.  Signaling through the 
receptor is not needed for HIV entry, but it is not known whether HIV 
interaction with the receptors can initiate signaling, and whether this may 
contribute to cellular dysfunction.  

o  What factor(s) lead to enhanced virus replication in late stage disease or, 
conversely,  what factors might restrict virus but be lost as time goes on.  
Cytokine-mediated mechanisms may be among the factors that upregulate and 
limit viral growth. 

o  The role of chemokines/cytokines in the pathogenesis of HIV-1-associated 
pulmonary co-infections, e.g. tuberculosis, P.carinii pneumonia and other 
bacterial and fungal pneumonias.

o  The role of chemokines/cytokines in the activation of HIV-1. 

These are examples only.  Investigators should not feel limited to the 
subjects mentioned above and are encouraged to submit other topics pertinent 
to the objectives of the RFA. 

Two additional goals of the RFA specific to the Mentored Quantitative Research 
Career Development Award, K25 awards, are as follows:

o   Encourage research-oriented quantitative scientists and engineers with 
little or no experience in biology or biomedicine to develop independent 
research skills and gain experience in advanced methods and experimental 
approaches that will allow them to conduct basic or clinical biomedical 
research related to cytokine/chemokine networks in HIV-associated lung disease 
or to play leading roles in multi-disciplinary research teams. 

o  Increase the pool of quantitative researchers who can conduct biomedical 
research related to the genetic aspects of tuberculosis in the lung, 
capitalizing on the quantitative backgrounds of the investigators to inform 
new directions in this area of research. 

SPECIAL REQUIREMENTS

To be responsive to the RFA, applications must include plans and the necessary 
mathematical expertise to develop mathematical models of cytokine/chemokine 
networks in the lungs and address HIV or HIV-related disorders.  We are 
particularly interested in non linear models.  To the extent possible the 
models should be tested and validated.   

Applicants are strongly encouraged to include a major biological component.  
It is anticipated that close collaborations between mathematicians, bench 
scientists, clinical investigators, or epidemiologists will be needed.  
Multidisciplinary approaches that include biologic validation of the 
mathematical models are of particular interest.  Research in animal models is 
encouraged.  

The mathematical models may address cytokine/chemokine networks in the lung 
during HIV infection in humans or animal models of HIV infection (e.g. SIV 
infection, mouse models immunodeficient states).  Also responsive, are 
mathematical models of cytokine/chemokine networks in the lung involved in the 
pathogenesis of diseases frequently associated with HIV, including, but not 
limited to tuberculosis, Pneumocystis carinii pneumonia, and cryptococcosis.  
The cytokine/chemokine network models may also address interactions between 
HIV and other factors in the lung.  Examples include, but are not limited to 
HIV-tuberculosis interactions, HIV-cigarette smoke interactions, HIV-
pneumococcal pneumonia interactions, and lung reactions that occur during the 
treatment of HIV infection with antiretroviral agents. Grant applications that 
only address cytokine/chemokine networks in normal lungs are not acceptable, 
but may be used for comparisson.

Research on human tissue is encouraged.  However, large clinical or population 
based studies are not within the scope of this RFA. 

Each application submitted for this RFA must be a complete, independent entity 
and not depend on any other application submitted in response to this RFA.

K25 applicants must fulfill the eligibility requirements for the K25 award 
described at http://grants.nih.gov/grants/guide/pa-files/PA-99-087.html.  
Special requirements for the K25 award pertain to the candidate, the 
mentor(s), the program, the environment and possible future evaluations.
  
Upon initiation of the program, the NHLBI and NIBIB will sponsor periodic 
meetings to encourage exchange of information among all funded investigators 
who participate in this program.  A major goal of these meetings is to 
facilitate progress by providing a forum that will lead to sharing ideas, 
technology, data, skills, and biological materials.  Applicants for both K25 
and R01 awards must budget for travel funds that will allow principal 
investigators and other key research scientists to participate in these 
meetings.  The meetings are usually one day meetings, held each year, in 
Bethesda, Maryland. Applicants must include a statement in their applications 
indicating their willingness to participate in these meetings.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their sub-populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is provided indicating 
that inclusion is inappropriate with respect to the health of the subjects or 
the purpose of the research. This policy results from the NIH Revitalization 
Act of 1993 (Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.  
The amended policy incorporates: the use of an NIH definition of 
clinical research; updated racial and ethnic categories in compliance with the 
new OMB standards; clarification of language governing NIH-defined Phase III 
clinical trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; and 
b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects" that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address:  http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS

NIH policy requires education on the protection of human subject participants 
for all investigators submitting NIH proposals for research involving human 
subjects.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.  

LETTER OF INTENT 

Prospective applicants are asked to submit, by March 12, 2002, a letter of 
intent that includes a descriptive title of the proposed research, the name, 
address, and telephone number of the Principal Investigator, the identities of 
other key personnel and participating institutions, and the number and title 
of the RFA in response to which the application may be submitted. Although a 
letter of intent is not required, is not binding, and does not enter into the 
review of subsequent applications, the information that it contains allows 
NHLBI staff to begin to identify appropriate reviewers, to estimate the 
potential review workload and plan the review.  

The letter of intent is to be sent to Dr. Deborah P. Beebe listed under 
INQUIRIES by the letter of intent date listed.

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html must be 
used in applying for these grants. This version of the PHS 398 is available in 
an interactive, searchable format.  For further assistance contact GrantsInfo, 
Telephone 301/435-0714, Email:  GrantsInfo@nih.gov.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only when 
there is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and NIH staff. 
The research grant application form PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.  

Modular grant applications will request direct costs in $25,000 modules, up to 
a total direct cost of $300,000 (12 modules) per year for all R01s.  
Investigators working with non human primate models may submit modular grant 
applications (using $25,000 modules) for up to $450,000 (18 modules) direct 
costs.

Specific Instructions for K25 Applications

An important goal of this RFA is to stimulate collaborations between 
quantitative scientists and biological scientists to investigate the genetics 
of tuberculosis.  We want to encourage junior level quantitative biologists to 
do research on the mathematical models of chemokine/cytokine networks in HIV-
associated lung diseases.  For this reason the K25 program, which fosters 
career development of mathematicians and engineers interested in 
biomedical research, has been included as a funding mechanism under this RFA. 
 Some information on eligibility criteria for the K25 is summarized below.  
However, THOSE INTERESTED IN APPLYING FOR K25 AWARDS WILL NEED TO OBTAIN 
ADDITIONAL INFORMATION ON THE K25 GOALS, ELIGIBILITY, RESTRICTIONS AND SPECIAL 
REQUIREMENTS FROM THE K25 PROGRAM ANNOUNCEMENT, WHICH CAN BE FOUND AT: 
http://grants.nih.gov/grants/guide/pa-files/PA-99-087.html.

The K25 awards are NOT modular.  Applications for K25 awards under this RFA 
must use the RFA receipt date of April 12, 2002, NOT the application receipt 
dates stated in the PA-99-087.  The K25 application budgets should be prepared 
in accordance with the allowable costs and instructions provided in PA-99-087. 
The K25 applications must follow the K25 guidelines and comply with the 
requirements for the K25.  Just-in-time instructions apply to both the R01 and 
K25 mechanisms.

o Special eligibility requirements apply to K25 Candidates applying for this 
RFA: They must have demonstrated research interests with an advanced degree in 
a quantitative area of science or engineering: M.S.E.E., Ph.D., D.Sc., etc. 
They must identify a mentor with extensive biomedical and/or computational 
biology research experience.  The K25 candidates must be willing to spend at 
least 75 percent of full-time professional effort conducting research career 
development and basic or clinical research.  K25 applicants experience in 
biomedical research may vary.  Some may have very limited experience in 
biomedical research and require didactic training and a very closely 
supervised research experience.  Other K25 applicants, with more experience, 
may require less class work and less supervision.  Applications may be 
submitted on behalf of candidates, by DOMESTIC organizations, public or 
private, such as research foundations, research institutions, commercial 
entities, medical, dental, or nursing schools, Federal National Laboratories 
(except for laboratories of the National Institutes of Health), or other 
institutions of higher education.  At time of the K25 AWARD, CANDIDATES MUST 
BE CITIZENS OR NONCITIZEN NATIONALS OF THE UNITED STATES, OR HAVE BEEN 
LAWFULLY ADMITTED TO THE UNITED STATES FOR PERMANENT RESIDENCE (I.E., IN 
POSSESSION OF A CURRENTLY VALID ALIEN REGISTRATION RECEIPT CARD I-551, OR 
OTHER LEGAL VERIFICATION OF SUCH STATUS).   Noncitizen nationals are generally 
persons born in outlying possessions of the United States (i.e., American 
Samoa and Swains Island).  Individuals on temporary or student visas are not 
eligible.

o FORMER PRINCIPAL INVESTIGATORS on NIH research project (R01), program 
project (P01), center grants (P50, P60), FIRST Awards (R29), SBIR/STTR awards, 
sub-projects of program project or center grants, K01, K08 or K23 awards, or 
the equivalent are NOT ELIGIBLE FOR THE K25 AWARD. FORMER PRINCIPAL 
INVESTIGATORS of an NIH Small Grant (R03) or Exploratory/Developmental Grants 
(R21) REMAIN ELIGIBLE. A candidate for the Mentored Quantitative Research 
Career Development Award may not concurrently apply for any other PHS award 
that duplicates the provisions of this award nor have another application 
pending award. Mentored Quantitative Research Career Development Award 
recipients are strongly encouraged to apply for independent research grant 
support, either Federal or private, during the latter period of this K25 
award.  However, since the K25 is a full professional effort award, time 
conducting additional research directly related to this award is subsumed 
under the salary support already provided by this award.

The K25 Application Must Contain the Following:

Candidate (K25)

o  A description of the candidate's commitment to a career in quantitative 
biomedical, behavioral, or bioengineering research

o  Evidence of the candidate's interest in conducting research

o  Evidence of the candidate's potential to develop into an independent 
investigator

o  A description of immediate and long-term career objectives, explaining how 
the award will contribute to their attainment

o  A commitment of at least 75 percent effort to this research program

o  Three sealed letters of recommendation addressing the candidate's potential 
for a research career in quantitative biomedicine or bioengineering. The 
mentor's statement (see below) should not be included as one of the letters of 
recommendation, although the mentor(s) may submit a separate letter(s) of 
recommendation.

Career Development Plan (K25)

o  A description of the career development plan, incorporating consideration 
of the candidate's goals and prior experience.  It must describe a systematic 
plan to obtain the necessary theoretical and conceptual background, in 
addition to the research experience, necessary to launch an independent 
research career in quantitative biomedicine or bioengineering.

o  Candidates must describe the availability of courses important to their 
career development plan at their institution and the manner of integration of 
these studies into their career development plan.

o  The career development plan must be tailored to the needs of the individual 
candidate and the ultimate goal of achieving independence as a researcher in 
quantitative biomedicine or bioengineering.  Less experienced candidates may 
require a phased developmental period in which the first one to two year(s) of 
the award are largely of a didactic nature followed by a period of intense, 
supervised research. Candidates with more experience at the time of 
application may need a shorter developmental period and may already have an 
adequate theoretical background. 

o  Candidates must describe plans to receive instruction in the responsible 
conduct of research. These plans must detail the proposed subject matter, 
format, frequency, and duration of instruction.  No award will be made if an 
application lacks this component.

Research Plan (K25)

o  A description of the quantitative biomedical, behavioral, or bioengineering 
research plan. The research plan must be described as outlined in form PHS 
398, including sections on the Specific Aims, Background and Significance, 
Progress Report/Preliminary Studies, Research Design and Methods.  The 
candidate should consult with the mentor regarding the development of this 
section.

Mentor's Statement (K25)

o  The application must include information on the mentor(s), including 
information on basic or clinical biomedical research qualifications in the 
research area proposed by the candidate and previous experience as a research 
supervisor.  The application must also include information to describe the 
nature and extent of supervision that will occur during the proposed award 
period.  Mentors may be employed in any sector of the biomedical research 
community (e.g., academia, industry, non-profit research institutions). 

Environment and Institutional Commitment (K25)

o  The sponsoring institution must document a strong, well-established 
research and training program related to the candidate's area of interest, 
including a high-quality research environment with staff capable of productive 
collaboration with the candidate. The sponsoring institution also must provide 
a statement of commitment to the candidate's development into a productive, 
independent investigator. 

SUBMISSION PROCEDURES FOR ALL APPLICATIONS

The RFA label available in the PHS 398 (rev. 5/2001) application form 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/label-bk.pdf.

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
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application as well as 
all five collated sets of Appendix material must be sent to Dr. Deborah Beebe 
at the address listed under Inquiries.  Applications must be received by the 
application receipt date listed in the heading of this RFA. If an application 
is received after that date, it will be returned to the applicant without 
review.  

Applications must be received by the application receipt date listed in the 
heading of this RFA, April 12, 2002.  If an application is received after that 
date, it will be returned to the applicant without review. 

The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed.  This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an introduction addressing the previous critique. 

Principal investigators should not sent supplementary material without first 
contacting the Scientific Review Administrator (SRA).  The SRA will be 
identified in the letter sent to you indicating that your application has been 
received.  If you have not received such a letter within three weeks after 
submitting the application, contact Dr. Deborah Beebe at the address listed 
under Inquiries.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
for responsiveness by the NHLBI and NIBIB.  Incomplete and/or non-responsive 
applications will be returned to the applicant without further consideration. 

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 
the NHLBI in accordance with the review criteria stated below.  The roster of 
reviewers for the RFA will be available on the NHLBI home page approximately 
four weeks prior to the scheduled review date.  As part of the initial merit 
review, a process will be used by the initial review group in which all 
applications receive a written critique and undergo a process in which only 
those applications deemed to have the highest scientific merit, generally the 
top half of the applications under review, will be discussed, assigned a 
priority score, and receive a second level review by the National Heart, Lung, 
and Blood Advisory Council or the National Institute of Biotechnology and 
Bioengineering 
Advisory Council.

Review Criteria for R01 Applications

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written review, comments on the following aspects of the application will 
be made 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 the 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.

(1) Significance:   Does this study address an important problem?  If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that drive 
this field?

(2) Approach:   Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

(3) Innovation:   Does the project employ novel concepts, approaches or 
method?  Are the aims original and innovative?  Does the project challenge 
existing paradigms or develop new methodologies or technologies?

(4) Investigator:   Is the investigator 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 (if any)?

(5) Environment:   Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 
support?

Review Criteria for K25 Applications

The following review criteria will be applied:

Candidate

o  Quality of the candidate's academic and research record; 

o  Potential to develop as an independent quantitative biomedical or 
bioengineering researcher or to play significant role in multi-disciplinary 
research teams; and 

o  Commitment to a career in quantitative biomedical or bioengineering 
research.  

Career Development Plan

o  Likelihood that the career development plan will contribute substantially 
to the scientific development of the candidate;

o  Appropriateness of the content and duration of the proposed didactic and 
research phases of the award;

o  Consistency of the career development plan with the candidate's career 
goals and prior research experience; and

o  Quality of the proposed training in responsible conduct of research.

Research Plan

Reviewers recognize that an individual with limited research experience is 
less likely to be able to prepare a research plan with the breadth and depth 
of that submitted by a more experienced investigator.  Although it is 
understood that K25 applications do not require the level of detail necessary 
in regular research grant applications, a fundamentally sound research plan 
must be provided. In general, less detail is expected with regard to research 
planned for the later years of the award, but the application should outline 
the general goals for these years.

o  Appropriateness of the research plan to the stage of research development 
and as a vehicle for developing the research skills as described in the career 
development plan;

o  Scientific and technical merit of the research question, design and 
methodology;

o  Relevance of the proposed research to the candidate's career objectives;

o  Adequacy of the plan's attention to gender and minority issues associated 
with projects involving human subjects; and

o  Adequacy of plans for including children as appropriate for the scientific 
goals of the research, or justification for exclusion.

Mentor

o  History of research productivity and support in the area of basic or 
clinical biomedical research; 

o  Appropriateness of mentor's research qualifications in the area of this 
application;

o  Quality and extent of mentor's proposed role in providing guidance and 
advice to the candidate; and

o  Previous experience in fostering the development of researchers.

Environment and Institutional Commitment

o  Applicant institution's commitment to the scientific development of the 
candidate and assurances that the institution intends the candidate to be an 
integral part of its research program; 

o  Adequacy of research facilities and the availability of appropriate 
educational opportunities (including access to such facilities or 
opportunities in other institutions);

o  Quality and relevance of the environment for scientific and professional 
development of the candidate; and 

o  Applicant institution's commitment to an appropriate balance of research 
and other responsibilities.

In addition to the above criteria, in accordance with NIH policy, all R01 and 
K25 applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders and minorities and their 
subgroups as appropriate for the scientific goals of the research will be 
reviewed.  Plans for the recruitment and retention of subjects will also be 
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project 
proposed in the application.

SCHEDULE

Letter of Intent Receipt Date:  March 12, 2002
Application Receipt Date:       April 12, 2002
Review:                         June/July 2002
Council Review:                 September 5-6, 2002
Anticipated Start Date:         September 30, 2002

AWARD CRITERIA

Award criteria that will be used to make award decisions include:
o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.

Applicants should be aware that, in addition to scientific merit, program 
priorities and program balance, the total costs of the proposed project and 
the availability of funds will be considered by the awarding Institutes in 
making funding recommendations.  The Institutes may fund individual 
applications based on a number of considerations, the most important of which 
are based on their scientific merit and their importance in meeting the 
objectives of the RFA.  Applications from new investigators will be strongly 
considered.

INQUIRIES

Inquiries concerning this RFA are strongly encouraged.  Potential applicants 
should request a copy of the sample budget pages. The opportunity to clarify 
any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:
Hannah H. Peavy, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0222
FAX:  (301) 480-3557
E-mail:  peavyh@nih.gov

Or

Sandra Colombini Hatch, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0222
FAX:  (301) 480-3557
E-mail:  hatchs@nhlbi.nih.gov

Or

Joan T. Harmon, Ph.D.
Division of Bioengineering
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Building 31, Room  1B37, MSC 2077
Bethesda, MD  20892
Telephone:  (301) 451-6772 
FAX:  (301) 480-4515
Email:  harmonj@nibib.nih.gov

Direct inquiries regarding fiscal matters (e.g., sample budget pages) to:

Raymond Zimmerman
Division Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7158, MSC 7926  
Bethesda, MD  20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
Email:  ZimmermR@nhlbi.nih.gov

Inquires regarding review, letters of intent and two copies of the grant 
application should be directed to:

Deborah P. Beebe, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0270
FAX:  (301) 480-3541
E-mail:  beebed@nhlbi.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance, Nos. 
93.838 and 93.361.  Awards are made under authorization of Sections 301 and 
405 of the Public Health Service Act as amended (42 UC241 and 284) and 
administered under PHS grants policies and Federal Regulations 42 CFR 52 and 
45 CFR Parts 74 and 72 and CFR 52 and 45 CFR Part 74 for NIAID. This program 
is not subject to the intergovernmental review requirements of Executive Order 
12372 or a Health Systems Agency Review.

The PHS strongly encourages all grant and contract recipients to provide a 
smoke-free workplace and promote the non-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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