STRATEGIES TO AUGMENT ALVEOLIZATION

Release Date:  April 17, 1998

RFA:  HL-98-011

P.T.

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date: June 15, 1998
Application Receipt Date: September 4, 1998

THIS REQUEST FOR APPLICATIONS (RFA) USES "MODULAR GRANT" AND "JUST-IN-TIME"
CONCEPTS AND INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS
AND MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

This solicitation invites research grant applications focused on regulation of
alveolar formation in the lung. The goal of the program is to generate genetic,
cellular and molecular information about alveolar formation that will ultimately
lead to the development of rational clinical interventions in aberrant lung
development, injury, or disease processes.

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 RFA, Strategies to Augment
Alveolization, is related to the priority areas of maternal and infant health,
chronic disabling diseases, and tobacco.  Potential applicants may obtain a copy
of "Healthy People 2000" (Full Report:  Stock No.017-001-00474-0 or Summary
Report:  Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

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.  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.

Among the disciplines and expertise that may be appropriate for this program are 
developmental biology, molecular biology, physiology, molecular genetics,
biochemistry, pharmacology, morphometry, pathology, pediatrics and pulmonary
medicine.

MECHANISM OF SUPPORT

This RFA will use the NIH individual research project grant (R01) mechanism of
support. Investigators without prior R01 support are encouraged to apply for this
RFA and to identify their status as a new investigator in a cover letter. 
Specific R01 application instructions have been modified to reflect "MODULAR
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.  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, applicant institutions, reviewers, and Institute
staff.  Although multi-disciplinary 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.

For this RFA, funds must be requested in $25,000 direct cost modules and a
maximum of eight modules ($200,000 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.  Instructions for completing the Biographical Sketch
have also been modified.  In addition, Other Support information and the
application Checklist page are not required as part of the initial application. 
If there is a possibility for an award, necessary budget, Other Support and
Checklist information will be requested by NHLBI staff following the initial
review. The APPLICATION PROCEDURES section of this RFA provides specific details
of modifications to standard PHS 398 application kit instructions.

FUNDS AVAILABLE

It is anticipated that for fiscal year 1999, approximately $2,500,000 total costs
will be available for the first year of support for this initiative.  Award of
grants pursuant to this RFA is contingent upon receipt of such funds for this
purpose.  It is anticipated that approximately  8 new grants will be awarded
under this program.  The specific number to be funded will, however, depend on
the merit and scope of the applications received and on the availability of
funds.  Direct costs will be awarded in modules of $25,000, less any overlap or
other necessary administrative adjustments. Facilities and Administrative costs
will be awarded based on the negotiated rates.

RESEARCH OBJECTIVES

Background

Three major lung diseases are characterized by the presence of too few alveoli
for normal gas exchange: emphysema, diffuse interstitial fibrosis, and
bronchopulmonary dysplasia (BPD).  Alveolar destruction is the main recognized
cause of þalveolar insufficiencyþ in emphysema and in interstitial fibrosis.  In
BPD, there is impaired septation that, along with alveolar destruction,  results
in too few alveoli for adequate gas exchange.  Other less common causes of
alveolar destruction that result in inadequate gas exchange include pulmonary
tuberculosis, sarcoidosis, other granulomatous diseases, and several occupational
lung.

Unlike the liver, which can regenerate in response to destruction, there has been
no indication that the lung can regenerate destroyed alveoli, either
spontaneously or by means of pharmacologic induction.  Thus, the only remediation
for individuals with too few alveoli for life-sustaining gas exchange is lung
transplantation.

However, recent investigations have, for the first time, suggested that
pharmacologic-induced generation of alveoli is indeed possible.  Treatment with
all-trans retinoic acid induces formation of increased numbers of alveoli in
lungs of neonatal rats where it also prevents the inhibition of alveolus
formation by corticosteroid hormones.  The ability of retinoic acid to induce
alveolar septation has also been demonstrated with fetal murine lungs in culture. 
In adult rats, retinoic acid abrogates key features of emphysema (i.e., larger
but fewer alveoli and increased lung volume) in an elastase-generated model of
the disease.  Whether retinoic acid treatment results in improved lung function
and gas exchange is not yet known; nor is the cellular and molecular basis of the
effects of retinoic acid on lung alveoli understood.  Yet these results provide
a first glimpse at the possibility of regenerating lost alveoli by pharmacologic
means.

The cellular and molecular events regulating septation and alveolar formation in
the developing and postnatal  lung are not well characterized.  The role of
potential suppressive signals and the responding genes that may exist to
terminate the process of septation and alveolar formation are virtually unknown. 
Identifying genes that play a role in suppressing alveolar formation is important
for understanding conditions in which unregulated growth of alveoli might be
directed toward repair of lung injury in the adult.

It is clear from studies of liver regeneration that signals originating in
extrahepatic organs play a key role in hepatic regeneration.  It is especially
instructive in this regard that liver size is tightly tied to body size; a liver
from a small animal transplanted into a large animal grows to become
proportionate to the body size of the recipient; the reverse occurs when a liver
from a large animal is transplanted into a small animal.  Thus, extrahepatic
signals have a critical role in liver regeneration and in establishing liver
size.

Similarly, extra-pulmonary factors regulate the formation of pulmonary alveoli
as corticosteroid impair and thyroid hormones accelerate the formation of alveoli
in newborn rats.  Likewise, thyroid hormone-induced increases in metabolic rate
in adult animals are associated with increased alveolar surface area and probably
increased alveolar number. It is clear from these observations that regulation
of genetic transcription is complex and involves a hierarchy of other factors as
well.  However, the cascade of signal molecules and receptors which govern this
hierarchy provides many opportunities for interaction, both spatial and temporal,
between regulatory genes and signals with both positive and negative effects. 
It is within this hierarchical context that new opportunities for clinical
intervention like that observed for trans-retinoic acid are likely to emerge.

Whether retinoic acid treatment results in improved lung function and gas
exchange remains to be determined by further morphogenic, pharmacologic and
physiologic studies.  It is likely that other pharmacologic agents could elicit
similar responses and/or ensure functional status for the newly formed
structures, perhaps by stimulating their vascularization.  However, as the
science of retinoic acid action in the regulation of alveolar formation is
explored, gaps in our knowledge of the process of alveolization will be uncovered
and important signal molecules will likely be identified.  From studies of the
genes induced by retinoic acid we should be able to gain insight into whether
remodeling and development utilize the same pathways.

Studies designed to clarify the reversibility of the retinoic acid effect and the
activity of other retinoid analogues, agonists, and antagonists in the process
of alveolarization will likely uncover other, non-pulmonary systemic agents which
induce formation of alveoli.  There is reasonably clear evidence that agents
expected to alter the lung matrix, e.g., collagenase, growth factors and other
transcription factors affect the formation of alveoli.  Environmental conditions
also influence the formation of alveoli.  Oxygen tension is involved in the
formation of alveoli and hypoxia exerts a developmentally dependent influence
which may be important for alveolization and lung function in individuals born
at high altitude. Emphysema-like lesions can be readily induced in rodents by
protein-reduced diets, in the absence of any evidence of inflammatory cell
accumulations. However, the molecular signals and responsive genes involved in
all these observable effects are, as yet, unknown. Fundamental studies of lung
alveolar formation also have the potential to re-direct effort to prevention as
well as repair should a genetic pre-disposition or biochemical predictor of
alveolar destruction be uncovered.

Objectives and Scope

The objective of this initiative is to encourage studies to define the principles
which determine the possibilities for regeneration of lung alveoli. However,
since opportunities for repair of damaged tissue in the lung are still poorly
understood, research could be directed at understanding the normal mechanisms
underlying the formation and functional differentiation of alveoli during
development as a framework for understanding the potential to improve the
abnormal condition.  For example, projects are encouraged that aim to define the
molecular events regulating septation and alveolar formation in the developing
and postnatal lung.  Likewise, the role of suppressive signals and the responding
genes that may exist to terminate the process of septation and alveolar formation
would be of interest as would identification of extra-pulmonary factors involved
in the regulation of alveolar formation and regeneration.

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

*  identification of genes induced by retinoic acid;
*  identification of stem cells and markers for septal formation during
alveolization;
*  identification of genes involved in regulating septation;
*  identification and characterization of the retinoic acid receptors involved
in alveolization;
*  regeneration of alveoli in animal models of emphysema;
*  assessment of the activity of retinoid analogues, agonists, and antagonists
on alveolization;
*  retinoic acid storage and secretion by lung fibroblasts during alveolization;
*  assessment of functional status of newly formed alveoli;
*  assessment of the reversibility of the retinoic acid effect on increased
septation;
*  relevance of tissue levels of retinoic acid for alveolization in premature and
normal infants and in adults;
*  comparison of the efficacy of retinoic acid with other morphogenic agents
which may effect the formation of alveoli;
*  toxicity assessment of concentrations of retinoic acid which effect
alveolization.

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.  It is anticipated that human, animal, and in vitro
studies would be appropriate.

SPECIAL REQUIREMENTS

Upon initiation of the program, the NHLBI will sponsor periodic meetings to
encourage exchange of information among investigators who participate in this
program.  In the budget of the grant application, travel funds for a one day
meeting each year, most likely to be held in Bethesda, Maryland, should be
included in the modules.  Applicants should also include a statement in their
applications indicating their willingness to participate in these meetings.

Applications concerned with global processes involved in normal lung development
are not acceptable.  The intent of this program is to focus on the specific
generation of alveoli and, therefore, studies of normal alveolar development and
its regulation may be included.  Applications that propose descriptive studies
and do not contain hypothesis driven studies directed at understanding the
mechanisms that influence alveolization  and its regulation will not be
acceptable.  Applications that focus on positive effectors of alveolization at
the molecular level are of particular interest.  Although studies in human
subjects are strongly encouraged, large clinical studies are not within the scope
of this RFA.  Applicants who propose to test hypotheses in animal, in vitro
models must provide a strong rationale for relevance to the human host.  This
program will not support studies directed at development of animal models alone.

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
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

All investigators proposing research involving human subjects should follow 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 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 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 June 15, 1998, 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 faxed or sent to Dr. C. James Scheirer, at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used for
applying for these grants.  These forms are available at most institutional
offices of sponsored research and may be obtained from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email:
ASKNIH@od.nih.gov.

Sample budgets and justification page will be provided upon request or following
the submission of a letter of intent.

BUDGET INSTRUCTIONS - The total direct costs must be requested in accordance with
the program guidelines and the modifications made to the standard PHS 398
application instructions described below:

o  FACE PAGE - As a reminder, Item 7 should be completed to indicate Modular
Direct Costs requested and Item 8 should reflect Total Costs (Modular Direct plus
F&A costs).

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398 (rev 5/95).  It is not required nor will it be accepted at the
time of application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget tables on Form page 5 of the PHS 398 (rev. 5/95).  Only the
requested total direct costs line for each year must be completed based on the
number of $25,000 modules being requested.  Applicants may not request a change
in the amount of each module.  A maximum of EIGHT modules ($200,000 direct costs)
per year may be requested and each applicant may request up to four years of
support for this RFA.  Direct cost budgets will remain constant throughout the
life of the project (i.e., the same number of modules requested for all budget
periods).  Any necessary escalation should be considered when determining the
number of modules to be requested.  However, in the event that the number of
modules requested must change in any future year due to the nature of the
research proposed, appropriate justification must be provided.  Total Direct
Costs for the Entire Proposed Project Period should be shown in the box provided.

o  BUDGET JUSTIFICATION

-  Budget justifications should be provided under "Justifications" on Form Page
5 of the PHS  398.
-  List the names, role on the project and proposed percent effort for all
project personnel (salaried or unsalaried)and provide a narrative justification
for each person based on his/her role on the project.  Under the justification
for the principal investigator, indicate if you are a new investigator (i.e., an
investigator without prior R29 or R01 support).
-  Identify all consultants by name and organizational affiliation and describe
the services to be performed.
-  Provide a general narrative justification for individual categories
(equipment, supplies, etc.) required to complete the work proposed.  More
detailed justifications should be provided for high cost items.  Any large
one-time purchases, such as large equipment requests, must be accommodated within
these limits.

o  CONSORTIUM/CONTRACTUAL COSTS - 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.  Only the percentage of the
consortium/contractual TOTAL COSTS (direct and F&A) relative to the total DIRECT
COSTS of the overall project needs to be stated at this time. The following
example should be used to indicate the percentage cost of the consortium, "The
consortium agreement represents 27% of overall $175,000 direct costs requested
in the first year."  A budget justification for the consortium should be provided
as described in the "Budget Justification" section above (no Form Page 5 required
for the consortium).  Please indicate whether the consortium will be in place for
the entire project period and identify any future year changes in the percentage
relative to the parent grant.

If there is a possibility for an award, the applicant will be requested to
identify actual direct and indirect costs for all years of the consortium. Please
note that total subcontract costs need not be calculated in $25,000 modules. 
However, when subcontract funds are added to the parent grant budget, the total
direct cost amount must be included in the number of $25,000 modules requested.

o  BIOGRAPHICAL SKETCH - A biographical sketch is required for all key personnel,
following the modified instructions below.  Do not exceed the two-page limit for
each person.
-  Complete the educational block at the top of the form page;
-  List current position(s) and those previous positions directly relevant to the
application;
-  List selected peer-reviewed publications directly relevant to the proposed
project, with full citation;
-  The applicant has the option to provide information on research projects
completed and/or research grants participated in during the last five years that
are relevant to the proposed project.

o  OTHER SUPPORT - Do not complete the "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 if there is a possibility for an
award.

o  CHECKLIST - No "Checklist" page is required as part of the initial
application.  A completed Checklist will be requested by NHLBI staff if there is
a possibility for an award.

o  The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information is
necessary following the initial review.

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE
TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.

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

Submit a signed, typewritten original of the application 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 must be sent
to Dr. C. James Scheirer at the listing under INQUIRIES.

Applications must be received by September 4, 1998.  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.

REVIEW CONSIDERATIONS

Applications will be reviewed for completeness by the CSR and for responsiveness
by NHLBI.  Incomplete and/or nonresponsive applications will be returned to the
applicant without further review.  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 NIH peer review
procedures.  The personnel category will be reviewed for appropriate staffing
based on the requested percent effort.  The direct costs budget request will be
reviewed for consistency with the proposed methods and specific aims.  Any
budgetary adjustments recommended by the reviewers will be in $25,000 modules. 
The duration of support will be reviewed to determine if it is appropriate to
ensure successful completion of the requested scope of the project.

Review Criteria

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 the assignment of the overall score.

(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?

In addition, 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.

The initial review group will also examine the provisions for the protection of
human and animal subjects, the safety of the research environment, and
conformance with the NIH Guidelines for the Inclusion of Women and Minorities as
Subjects in Clinical Research.

The roster of the initial review group will be available via the NHLBI homepage.

AWARD CRITERIA

The following will be considered in making funding decisions: quality of the
proposed project as determined by peer review, availability of funds, and program
priority.  Applications from new investigators will be strongly considered.

The anticipated date of award is April 1,1999.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The application is available on
the NHLBI home page at the following address:
http://www.nhlbi.nih.gov/nhlbi/nhlbi.htm.  Potential applicants may request a
copy of sample budget and justification pages, as previously stated.  The
opportunity to clarify any issues or questions from potential applicants is
welcome.

Direct inquiries regarding programmatic issues to:

Mary Anne Berberich, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive Room 10102
Bethesda, MD  10892
Telephone:  (301) 435-0222
FAX:  (301) 480-3557
Email:  

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

Raymond L. Zimmerman
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7154, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
Email:  zimmermr@gwgate.nhlbi.nih.gov

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

C. James Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3541
Email:  james_scheirer@nih.gov

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 U.S.C. 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 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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