Full Text HL-95-002

MECHANISMS OF POST BONE MARROW TRANSPLANTATION LUNG INJURY

NIH GUIDE, Volume 23, Number 33, September 16, 1994

RFA:  HL-95-002

P.T.


Keywords: 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  December 1, 1994
Application Receipt Date:  January 19, 1995

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) invites research
grant applications to support of research on immunological, cellular,
and molecular mechanisms of post bone marrow transplantation lung
injury.  The primary objectives of this special grant program are to
determine the etiology and to understand the cellular and molecular
mechanisms involved in the pathogenesis of idiopathic pneumonia
syndrome (IPS) that frequently follows bone marrow transplantation.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Mechanisms of Post Bone Marrow Transplantation
Lung Injury, is related to the priority areas of immunization and
infectious diseases and cancer.  Potential applicants may obtain a copy
of "Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0) or
"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Among the disciplines and expertise that may be appropriate for this
research program are cell biology, virology, pharmacology, radiation
biology, molecular biology, immunology, molecular immunology,
infectious diseases, pathology, pulmonary medicine, pediatrics,
oncology, and hematology.

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 or local governments,
and eligible agencies of the Federal government.  Applications from
minority individuals, women, and new investigators are encouraged.

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 program will be awarded using an incremental funding method being
tested by the NIH.  Refer to the special instructions below and in the
APPLICATION PROCEDURES section.  Funds must be requested in increments
of $50,000 each (direct costs), or applications will be returned.

This RFA will use the NIH individual research project grant (R01)
support mechanism.  However, specific application instructions have
been modified to reflect streamlining efforts being examined by the
NIH.  It is hoped that these changes will reduce the administrative
burden for the applicants, reviewers, and NHLBI staff.  Up to four
years of support may be requested for these R01s.

For this RFA, funds must be requested in $50,000 direct cost increments
and a maximum of four increments ($200,000 direct costs) per year may
be requested.  Only limited budget information will be required and any
budget adjustments made by the Initial Review Group will be in
increments of $50,000.  Instructions for completing the Biographical
Sketch have also been modified.  In addition, Other Support information
and the application Checklist page will be requested by NHLBI staff
upon consideration for an award.  The APPLICATION PROCEDURES section of
this RFA provides specific details of modifications to standard
application instructions.

Upon initiation of the program, the NHLBI will sponsor periodic
meetings to encourage exchange of information among investigators who
participate in this program.  Applicants should also include a
statement in their applications indicating their willingness to
participate in a 1-day meeting each year, most likely to held in
Bethesda, Maryland.  Travel costs for these meetings are to be covered
by the grant.

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.

Applicants (who will plan and execute their own research programs) are
expected to furnish their own estimates of time required to achieve the
objectives of the proposed research project.  Since a variety of
approaches would represent valid responses to this RFA, it is
anticipated that there will be a range of costs among individual grants
awarded.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications may be submitted for peer review and
competition for support through the regular grant program of the NIH.
It is anticipated that support for this program will begin in August
1995.  Administrative adjustments in project period and/or amount may
be required at the time of the award.

While 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.

The National Institute of Allergy and Infectious Diseases (NIAID) also
has interest in the immunological/inflammatory/infectious aspects of
post bone marrow transplant injury.  Therefore, applications that are
of mutual interest are likely to be given a secondary assignment to
NIAID in accordance with the NIH referral guidelines.

FUNDS AVAILABLE

Approximately $1,500,000 total costs will be available for the first
year of support for the entire program, and is included in the
financial plans for fiscal year 1995; but, award of grants pursuant to
this RFA is contingent upon receipt of funds for this purpose.  It is
anticipated that no more than eight awards will be issued under this
program.  The specific number to be funded will, however, depend on the
merit and scope of the applications received and the availability of
funds.  Funds will be awarded in lump sum direct cost amounts in
increments of $50,000, less any overlap or other necessary
administrative adjustments.  Indirect costs will be awarded based on
the negotiated rate at the time of each award.

RESEARCH OBJECTIVES

Background

Bone marrow transplantation offers potentially curative treatment for
a growing number of patients with a variety of diseases.  Advances in
transplant immunobiology, supportive care and the availability of
suitable donors, make the technique both effective and feasible.  In
1990 statistics from the International Bone Marrow Transplant Registry
indicated that over 5,500 patients received allogeneic marrow
transplants from matched or partially matched family members and more
than 5,000 autologous transplant procedures were performed world wide.
Through the National Marrow Donor Program, it is now possible to
identify unrelated phenotypically HLA-matched donors for patients who
do not have suitable donors among family members.  Currently, more than
1,200,000 potential donors are registered in this program.  This number
doubled during the past two years.  Approximately 650 allogenic bone
marrow transplants involving unrelated donors and recipients were
performed in 1993.

In spite of these encouraging developments, transplantation-related
complications, especially those involving the lung, have limited the
success of bone marrow transplantation.  Interstitial pneumonitis is a
primary or contributing cause of mortality, accounting for more than 40
percent of deaths related to bone marrow transplantation in most large
series. Of these pneumonias, approximately half were attributed to
non-infectious idiopathic pneumonia syndrome (IPS).  It is also
possible that undetectable infectious agents are involved.  Although
progress has been made in diagnosis and treatment of infectious
pneumonia, e.g., cytomegalovirus (CMV) and Pneumocystis carinii, IPS
remains a major cause of morbidity and mortality.

For the purposes of this RFA the definition of IPS will be that
proposed in the NHLBI Workshop Summary: Idiopathic Pneumonia Syndrome
after Bone Marrow Transplantation (Am Rev Respir Dis
1993;147:1601-1606).

I.  Evidence of widespread alveolar injury.  Criteria include:
a.  Multilobar infiltrates on routine chest radiographs or CT scans.
b.  Symptoms and signs of pneumonia, e.g., cough, dyspnea, rales.
c.  Evidence of abnormal pulmonary physiology.
1.  Increased alveolar to arterial oxygen gradient (compared with
previous, if available).
2.  New or increased restrictive pulmonary function test abnormality.

II.  Absence of active lower respiratory tract infection.  Appropriate
evaluation includes:
a.  Bronchoalveolar lavage negative for significant bacterial pathogens
and/or lack of improvement with broad-spectrum antibiotics.
b.  Bronchoalveolar lavage negative for pathogenic nonbacterial
microorganisms.
1.  Routine bacterial, viral and fungal cultures.
2.  Shell-vial CMV culture.
3.  Cytology for CMV inclusions, fungi and Pneumocystis carinii.
4.  Detection methods for respiratory syncytial virus, parainfluenza
virus, and other organisms (e.g., fluorescent antibodies or culture).
c.  Transbronchial biopsy if condition of the patient permits.
d.  Ideally, a second confirmatory negative test for infection is done.
This usually is performed 2 to 14 days after the initial negative
bronchoalveolar lavage (BAL), and it may consist of a second BAL or an
open lung biopsy.

Although IPS is an important clinical entity, progress in understanding
the mechanisms underlying its pathogenesis has been limited.  The lack
of progress is partly due to lack of uniform definitions of the
disease, lack of uniform diagnostic criteria, and the relatively small
number of patients available for study at most centers.  These clinical
diagnostic obstacles are being overcome.  However, the fundamental
mechanisms that result in the development of IPS are still poorly
understood, even though the techniques for learning more about them are
now becoming available to researchers.  For example, there have been
major advances in basic immunology, molecular virology, radiation
biology and the biology of inflammation.  But, the application of this
knowledge to the problem of IPS has not been adequately pursued.

A better understanding of the immunological, cellular and molecular
basis of pathogenesis of post transplantation lung injury is needed to
identify those at risk and eventually treat or prevent this type of
lung tissue injury.  Examples of specific aspects of research that
would be encouraged under this initiative are as follows:  cellular and
biochemical mechanisms involved in the afferent phase of the
cell-mediated immune response; characterization and regulation of the
inflammatory cell population involved in IPS; assessment of the
capacity of resident lung cells, (for example, macrophages,
lymphocytes, epithelial and endothelial cells) to produce cytokines and
their role in generating the inflammatory and immune responses
associated with IPS; and immunopathologic roles of infectious agents.
These might include latent viral gene expression as it relates to
dysregulation of cytokine gene expression and alteration of immune
recognition and role of Gram negative bacterial products such as
lipopolysaccharide and other cell wall constituents.

Objectives and Scope

The overall objective of this initiative is to encourage basic research
on the etiology, mechanisms of pathogenesis, and the host determinants
that are involved in the initiation and progression of post bone marrow
transplantation lung injury.  Applications are invited for innovative
multidisciplinary approaches to identify the cause(s) of IPS associated
with bone marrow transplantation and to delineate cellular and
molecular mechanisms involved in its pathogenesis.  Applications
submitted in response to this RFA should clearly define the rationale,
background, and specific aims of the proposed studies, and should
provide a succinct description of the methods and procedures to be
used.  Several topics relevant to the objectives of this RFA are cited
below in order to provide a perspective of the scope of the research
that would meet the goals of the program.  Investigators are also
encouraged to consider approaches that meet the goals of this program
other than those cited below.

Since immune factors related to graft versus-host disease (GVHD) appear
to be significant risk factors for IPS, studies of IPS in animal models
of GVHD would be appropriate.  Several cytokines including TNF-alpha,
TNF-beta, IL-2, IL-4, and gamma-interferon may be involved in the
pathogenesis of GVHD.  Animal models of GVHD could be used in
mechanistic studies to look at cytokines and other factors associated
with IPS.  This might include lymphocyte-macrophage interactions as
they relate to the lung.  The work would have to focus on IPS; animal
models of GVHD alone, which are not pertinent to IPS, would not be
acceptable.  Other animal models of immune mediated lung disease (e.g.,
those involving adoptive transfer) might also be relevant.  It is
possible that knockout mouse models may be useful in delineating the
mechanisms involved in IPS.

The late stages of IPS are characterized by a fibroproliferative
reaction.  Mechanisms responsible for the cellular proliferation and
accumulation of collagen appear to involve interactions between
fibroblasts and effector molecules including platelet-derived growth
factor (PDGF), transforming growth factor beta (TGF-beta), and
insulin-like growth factor-I (IGF-I).  For instance, women receiving
autologous bone marrow transplantation for advanced breast cancer were
observed to have plasma TGF-beta levels that correlated strongly with
the risk of developing IPS.  More recently, TGF-beta has been observed
to induce the production of fibroblast-derived cytokines IL-6 and IL-11
and it is suggested that IL-11 may play an important role in the
pathogenesis of chronic inflammatory conditions including idiopathic
pulmonary fibrosis.  The ways in which these and related effector
molecules and cytokines participate in the pathogenesis of IPS might be
studied at the molecular level in cell systems and animal models.

Graft versus-host disease appears to increase host sensitivity to
endotoxin released in the gut.  It may be possible to adapt models of
GVHD to understand multiple causes of endothelial and epithelial
permeability and related events occurring in the lung.  For example,
models could be adapted to study the immunological response to Gram
negative bacteria, and responses to lipopolysaccharides and drugs as
they relate to IPS.

Latent viral gene expression as it relates to IPS could be studied in
animal models or cell systems.  Ways in which herpes viruses (e.g.,
CMV, EBV, HHV-6, etc.) and adenoviruses alter host cell regulation of
cytokine gene expression could be examined.  Other areas for
investigators might include the influence of latent viral infection on
the expression of cell surface receptors (e.g., ICAM) and responses to
antigens that may be triggered when viral genes are expressed.

The ability to make significant progress in understanding the basic
mechanisms involved in IPS would be greatly enhanced by adaptation of
animal models, especially small laboratory animals.  For example,
inbred strains might be used to learn about genetic determinants of
post bone marrow transplantation lung injury, and models of
pneumonitis, including CMV pneumonitis, might be helpful in determining
the role of cytokine-mediated lung injury related to IPS.

In addition to animal studies, innovative studies using human cells or
tissues which can be obtained incidentally are desirable.  Research
involving human subjects should be formulated in the context of
mechanistic studies and should address specific hypotheses.  Large
scale clinical studies are beyond the scope of this RFA.

SPECIAL REQUIREMENTS

Applications that propose descriptive studies and do not contain
studies directed at uncovering mechanisms of disease or supporting
hypotheses related to mechanisms of disease will not be acceptable.
This program will not support studies directed at development of animal
models alone.  Models must be applied to the study of disease
mechanisms associated with post bone marrow transplantation lung
injury.  Applications that focus on molecular biology and molecular
immunology of these disorders are of particular interest.

STUDY POPULATIONS

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 subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43)
and supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in Study Populations, and Concerning the Inclusion
of Minorities in Study Populations), which have been in effect since
1990.  The new policy contains some provisions that are substantially
different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH Guide for Grants and Contracts of March 18, 1994, Volume 23,
Number 11.

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

LETTER OF INTENT

Prospective applicants are asked to submit, by December 1, 1994, 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 estimate the potential review workload and to avoid conflict
of interest in the review.

The letter of intent is to be sent to Dr. C. James Scheirer at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

Submit applications on form PHS 398 (rev. 9/91), the application form
for the traditional research project grant.  This form is available in
an applicant institution's office of sponsored research and from the
Office of Grants Information, Division of Research Grants, National
Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD
20892, telephone (301) 710-0267.  Use the conventional format for
research project grant applications and ensure the points identified in
the section, "Review Procedures and Criteria" are fulfilled.  To
identify the application as a response to this RFA, check "YES" on item
2a of page 1 of the application and enter the title "Mechanisms of Post
Bone Marrow Transplantation Lung Injury," HL-95-002.

Applicants are expected to conform to the 25-page limit as directed in
the application kit (PHS 398).  Appendices containing supporting
materials may be submitted with the application, but may not be used to
circumvent this requirement.  Exceptions to this page limit must be
explicitly granted by the scientific review administrator.

The following modifications are to be made to the standard PHS 398
application instructions:

o  INITIAL BUDGET PERIOD - Only the names of personnel and level of
effort should be itemized in the Personnel section of the "Detailed
Budget for the Initial Budget Period" (Form Page 4).  In addition,
generally list consultants, equipment, supplies, travel, patient care
activities, alterations and renovations and other needs, as
appropriate. No costs need be associated with these individual items or
categories.  If Consortium/Contractual Costs are requested, then the
"Subtotal Direct Costs" line should be completed and the
"Consortium/Contractual Costs" section should include all Contractual
direct, indirect, and total costs.  The "Total Direct Costs" line at
the bottom of the page must be completed based on the number of $50,000
increments being requested.  Applicants may not request a change in the
amount of each increment.  A maximum of four increments ($200,000
direct costs) per year may be requested.  Any large one-time purchases,
such as large equipment requests, must be accommodated within these
limits.  APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE
CONSIDERED UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT
FURTHER REVIEW.

o  A sample budget is available upon request from Dr. Peavy at the
number listed under INQUIRIES.

o  FUTURE BUDGET PERIODS - It is anticipated that direct cost budgets
will remain constant throughout the life of the project (i.e., the same
number of increments requested for all budget periods).  Any necessary
escalation should be considered when determining the number of
increments to be requested.  However, in the event that the number of
increments changes in any future year, appropriate justification must
be provided.  The "Budget for Entire Proposed Project Period" (top
section of Form Page 5) should include Total Direct Costs for each year
and the Total Direct Costs for the Entire Proposed Project Period.  If
Consortium/Contractual Costs are requested, then the "Subtotal Direct
Costs" and the "Consortium/Contractual Costs" lines should be
completed.  In addition, the Justification section should be completed
based on instructions provided on Form Page 5.

o  SUBCONTRACTS - If collaborations or subcontracts are involved that
require transfer of funds from the grantee to other institutions, it is
necessary to establish formal subcontract agreements with each
collaborating institution.  A letter of intent from each collaborating
institution should be submitted with the application.  Budgets for
subcontracts should be prepared using the same guidelines as for the
main grant except that total subcontract costs need not be in $50,000
increments.  Requested amounts should be based on individual needs of
the subcontract and should reflect both direct and indirect costs.
When subcontract funds are added to the main grant budget, the total
amount must conform with the number of $50,000 increments requested.

o  BIOGRAPHICAL SKETCH - In addition to the standard information
requested on Form Page 6, the applicant has the option of providing the
title and source of any sponsored support relevant to the proposed
research.

o  OTHER SUPPORT - No other support information is required on "Other
Support" pages (Form Page 7).  Selected other support information
relevant to the proposed research may be included in the Biographical
Sketch as indicated above. Complete other support information will be
requested by NHLBI staff upon consideration for an award.

o  CHECKLIST - No "Checklist" page is required as part of the
application.  A completed Checklist page will be requested by NHLBI
staff upon consideration for an award.

The RFA label available in the PHS 398 application kit must be affixed
to the bottom of the face page of the original completed application
form PHS 398.  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.

Send or deliver the completed application and three signed photocopies
in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Send two additional copies of the application to:

C. James Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 557
Bethesda, MD  20892

It is important to send these two copies at the same time as the
original and three copies are sent to the Division of Research Grants
(DRG).  Otherwise the NHLBI cannot guarantee that the application will
be reviewed in competition for this RFA.

Applications must be received by January 19, 1995.  If an application
is received after this date, it will be returned to the applicant
without review.  The DRG 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
DRG 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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the DRG
and responsiveness to this RFA by the NHLBI. Incomplete applications
will be returned without further consideration.  Applications that are
complete and responsive will be evaluated for scientific and technical
merit by a special emphasis panel, convened by the Division of
Extramural Affairs, NHLBI, solely to review these applications.

As part of the initial merit review, a process (triage) may be used by
the initial review group in which applications will be determined to be
competitive or non-competitive based on their scientific merit relative
to other applications received in response to the RFA.  Applications
judged to be competitive will be discussed and be assigned a priority
score.  Applications determined to be non-competitive will be withdrawn
from further consideration and the Principal Investigator and the
official signing for the applicant organization will be notified.

Review Criteria.  The factors to be considered in the evaluation of
scientific merit of each application will be similar to those used in
the review of traditional research project grant applications including
the novelty, originality, and feasibility of the approach; the
training, experience, and research competence of the investigator(s);
the adequacy of the experimental design; the suitability of the
facilities; and the appropriateness of the requested budget to the work
proposed.

The personnel category will be reviewed for appropriate staffing based
on the requested percent effort and any changes requested in future
years.  The budget request will be reviewed for consistency with the
proposed methods and specific aims.  The duration of support will be
reviewed to determine of it is appropriate to ensure successful
completion of the recommended scope of the project.

AWARD CRITERIA

The anticipated date of award is August 1, 1995.  In addition to the
scientific merit of the applications, awards will be based on the
availability of resources and program priorities.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
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
Westwood Building, Room 6A09
Bethesda, MD  20892
Telephone:  (301) 594-7425
FAX:  (301) 594-7487

Direct inquiries regarding review matters, address the letter of
intent, and mail two copies of the application to:

C. James Scheirer, Ph.D.
National Heart, Lung, and Blood Institute
Westwood Building, Room 557
Bethesda, MD  20892
Telephone:  (301) 594-7478
FAX:  (301) 594-7407

Direct inquiries regarding fiscal matters to:

Raymond L. Zimmerman
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A17
Bethesda, MD  20892
Telephone:  (301) 594-7420
FAX:  (301) 594-7492

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 93.838.  Awards are made under authorization of the Public Health
Service Act, Title IV, Part A (Public Law 78-410, amended by Public Law
99-158, 42 USC 241 and 285) and administered under PHS grants policies
and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This program is
not subject to the intergovernmental review requirements of Executive
Order 12372 or to review by a Health Systems Agency.

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use of
all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of American people.

.

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