Full Text HL-97-001
 
HOST FACTORS CONTROLLING INDIVIDUAL SUSCEPTIBILITY TO HIV-ASSOCIATED
PULMONARY DISEASE
 
NIH GUIDE, Volume 26, Number 1, January 10, 1997
 
RFA:  HL-97-001
 
P.T. 34

Keywords: 
  AIDS 
  Pulmonary Diseases 
  Infectious Diseases/Agents 

 
National Heart, Lung, and Blood Institute
 
Letter of Intent Receipt Date:  March 14, 1997
Application Receipt Date:  April 30, 1997
 
THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  THIS RFA
INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS
AND MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.
 
PURPOSE
 
The National Heart, Lung, and Blood Institute (NHLBI) invites
research grant applications for support of research on the cellular
and molecular mechanisms that influence host susceptibility to
HIV-associated lung diseases, including tuberculosis, histoplasmosis,
coccidioidomycosis, blastomycosis, Pneumocystis carinii pneumonia,
and pulmonary Kaposi's sarcoma.  The host factors could include
inherited traits, acquired immune responses, and environmental
influences.  Research could be directed at understanding normal host
defenses as a framework for understanding abnormal defenses.
 
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), Host Factors Controlling Individual
Susceptibility to HIV-associated Pulmonary Disease, is related to the
priority area of immunization and infectious diseases.  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.
 
MECHANISM OF SUPPORT
 
This RFA will use the NIH individual research project grant (R01)
mechanism of support. Investigators without prior R29 or R01 support
are encouraged to apply for this RFA and to identify their status 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.
 
While multidisciplinary approaches are encouraged, it is not the
intent of this announcement 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.
 
Applicants 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. Up to five years of support may be
requested on R01 applications.
 
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.  It is anticipated that support for
this program will begin in September, 1997.  Administrative
adjustments in project period and/or amount may be required at the
time of the award.
 
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.
 
The National Institute of Allergy and Infectious Diseases (NIAID)
also has interest in host factors that influence susceptibility to
infectious diseases.  Therefore, applications that are of mutual
interest are likely to be given a secondary assignment to NIAID in
accordance with the NIH referral guidelines.  A program announcement
"Innovative Drug Discovery Research in AIDS Opportunistic Infections"
(PA-96-068), NIH Guide Vol. 25, No. 26, August 2, 1996, covers areas
of research complementary to this RFA and may be of interest to some
investigators.
 
FUNDS AVAILABLE
 
It is anticipated that for fiscal year 1997, approximately $2,000,000
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 eight 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. Indirect costs
will be awarded based on the negotiated rates.  Applicants may
request up to five years of support.
 
RESEARCH OBJECTIVES
 
Background
 
Pulmonary disease associated with HIV infection continues to be a
major cause of morbidity and mortality.  Our knowledge of the host
factors and mechanisms involved in the defense against pulmonary
disease, including Mycobacterium tuberculosis (Mtb), Pneumocystis
carinii, endemic fungal pathogens, and pulmonary Kaposi's sarcoma, in
the HIV-infected host is still limited.  The contribution of host
factors appears to be important but is poorly understood at present.
To gain a better understanding of this area of science we need more
information on the host factors that restrict growth of microbes and
the establishment of Kaposi's sarcoma in the lungs of healthy
individuals, as well as how these factors function in those that are
immunodeficient.  For example, susceptibility to tuberculosis (TB) is
greatly increased among HIV-infected patients (approximately five
percent a year compared to 10 percent over a lifetime) but variable,
suggesting that factors other than low CD4 counts must be involved.
The factors that prevent individuals dually infected with HIV and Mtb
from developing active TB need to be determined.  Host genetic
factors, e.g., the natural resistance associated macrophage protein
(Nramp) gene, acquired immune responses, and environmental factors
(e.g., nutrition, smoking) appear to play a role.
 
Genetic variation as well as acquired changes in immune function may
affect many aspects of host defense against pulmonary diseases.
Receptors for uptake of Mtb are being identified, e.g., complement
receptors, mannose receptors and facilitation of uptake by surfactant
protein A  (SP-A).  A better understanding of these and other
"receptors" that microorganisms use for cellular penetration may
reveal genetic differences.  More information is needed on "receptor"
polymorphism, for example, different binding affinities might account
for some differences in individual susceptibility.  Similarly,
genetic differences as well as acquired immune responses may affect
the function of certain key cytokines necessary for control of
infection.  "Knock-out" and other mouse models indicate vital roles
for cytokines, e.g., tumor necrosis factor (TNF), gamma interferon
(INF), as well as other determinants, including intracellular killing
by nitric oxide, in control of Mtb.  A genetic factor, the human
Nramp has recently been cloned and expressed.  What role it may play
is unclear.  More information is needed about the genetic basis for
natural resistance and phenotypic expression of resistance genes in
the lung. Better animal models are needed now to understand the
complexities of innate and acquired resistance and the mechanisms of
latency and reactivation.
 
HIV-infected and other immunosuppressed hosts frequently develop
severe lung infections due to infection with fungi.  Among the most
important fungal agents are the endemic mycoses histoplasmosis,
blastomycosis and coccidioidomycosis.  An important feature shared by
all three is that the inhaled spores cannot be killed by neutrophils.
Moreover, prior to establishment of cell mediated immunity these
fungi are phagocytized by macrophages and neutrophils and continue to
propagate within these cells. Once cell mediated immunity develops in
the immunologically competent host, the infection is benign and self
limited.  However, in hosts with abnormal T-cell mediated immunity,
one can expect to see progressive and widely disseminated infection.
Thus, all three of these fungi are common opportunistic infections in
HIV infected patients.  Once these diseases are diagnosed in AIDS
patients, survival is poor (from a few days to up to three months),
even with treatment.
 
Histoplasmosis has complicated the course of Hodgkin's lymphoma,
corticosteroid and immunosuppressive treatment, but with the advent
of the HIV pandemic there has been a tremendous increase in the
number of patients with disseminated histoplasmosis.  Widely
disseminated disease occurs in two ways, by reactivation of
previously dormant infection in patients who appear to have recovered
from an earlier H. capsulatum infection, and as a result of
progressive disseminated primary infections. Blastomycosis also
complicates HIV infection in a manner analogous to histoplasmosis.
However, the number of cases is small and there is more frequent
involvement of the central nervous system.
 
Coccidioidomycosis/HIV co-infection is becoming increasingly more
common.  Most patients present with a rapidly progressive pulmonary
infection, frequently with a rapidly evolving reticulonodular
infiltrate seen on chest radiograph.
 
Treatment of endemic fungal infections in HIV-infected patients is
difficult and often requires large doses of amphotericin-B and other
drugs that have toxic side effects.  Large numbers of people are
infected with fungi in the endemic areas.  For example, in
Indianapolis the prevalence of clinical disease due to H. capsulatum
in the HIV-infected population is approximately 27 percent.
Management of severe fungal infections affecting HIV-infected
populations in areas endemic for fungi continues to be a difficult
clinical challenge.  Treatment of fungal infections might be improved
if genetic factors, which appear to be important determinants of
disseminated disease, were better understood.  Dissemination probably
occurs before immunity is established.  What allows it to occur, or
prevents it from happening?  An obstacle to learning about these
fungal diseases is the danger of working with the pathogens that
cause them.  These fungi, in their filamentous from, represent class
II (B. Dermatitidis) and class II (H. Capsulatum, C. Immitis)
biohazards, and therefore pose a risk of laboratory acquired
infection through inhalation of aerosols.
 
Pneumocystis carinii is an opportunistic organism that frequently
complicates the course of HIV disease.  In contrast to the other
infectious agents discussed, P. carinii, although it is cleared from
the lung by macrophages, is an extracellular pathogen which primarily
parasitizes Type I alveolar epithelial cells.  The organisms sit on
the surface of the Type I alveolar epithelial cells, but never get
inside.  However, the cells are damaged and slough off.  Recent
studies have focused on mechanisms of attachment of P. carinii to the
surface of the Type I cells and the role of SP-A.  Thus far, no
studies suggest mechanisms by which P. carinii organisms "parasitize"
the Type I alveolar epithelial cells.  What the organism gains from
living in the alveolar space on the surface of these particular cells
is not known.  Nor is it known, how this affects the life cycle of
these organisms.
 
Resistance of seemingly healthy/normal individuals to mycobacterial
and endemic fungal infections of the lung is extremely variable.  In
most infected persons, infections are mild and limited to the lung,
but in a few, disease is severe and sometimes disseminated.  Why does
disease disseminate in so few individuals?  It is likely that host
factors, especially genetic factors may play an important role.
Similarly, what host factors prevent the establishment of P. Carinii
infection in the lungs of healthy hosts and some immunosupressed
hosts?
 
Host resistance to mycobacteria, fungi and leishmania in mice all
appear to be influenced by genetic factors.  In mice infected with
leishmania, those with a strong Th1 response are resistant to
disease, but this can be reversed by giving the animals anti-INF
antibody.  The reverse experiments can be done too, i.e., animals
lacking a Th1 response can be made resistant to disease by giving INF
.  The leishmania locus may be the same as the Nramp locus.
Interestingly, patients with HIV and TB also lack the Th1 response,
as opposed to having an increased Th2 response.  A better
understanding of host resistance and susceptibility to all these
diseases could lead to better therapeutic strategies.
 
Expression of diseases in the lung, such as TB, Pneumocystis and
Kaposi's sarcoma may be directly affected by unique viral factors.
For example, HIV Tat protein was found to amplify the activity of
tumor necrosis factor (TNF) and in T cells the HIV Tat appears to
alter the redox state by suppressing the activity of manganese
superoxide dismutase.  Thus, the T-lymphocytes might be modulated by
this HIV-specific protein in a way that reduces their functional
capacity and facilitates expression of disease.
 
Objectives and Scope
 
The objective of this program is to understand at the molecular and
cellular level how host factors, both genetic and acquired, affect
susceptibility to a variety of HIV-associated infections and Kaposi's
sarcoma.  Research applicable to this initiative could include
studies of normal, nonspecific and specific host defenses to provide
a frame of reference for what occurs in the immunodeficient state;
and to understand why under "normal" conditions it is difficult to
produce Kaposi's and severe pulmonary infections (in humans and
animals).  Investigations might address how HIV infection and other
immunosupressed states affect innate resistance to pulmonary Kaposi's
sarcoma as well as mycobacterial, fungal and other pulmonary
infections.
 
Among the disciplines and expertise that may be appropriate for this
research program are microbiology, mycology, bacteriology, virology,
molecular biology, cell biology, immunology, molecular immunology,
infectious diseases, pathology, pulmonary medicine, and pediatrics.
 
Examples of areas of research (in HIV-infected, other immunodeficient
or "normal" human subjects, suitable animal models or in vitro
models) that might be included under this RFA are as follows:
 
o  investigate genetic factors that influence susceptibility to
severe infections of the lung with endemic fungal pathogens and to
dissemination of disease;
 
o  elucidate genetic or other factors within the host lung cells that
prevent or permit latency  and/or reactivation of Mtb;
 
o  Identify specific "receptors" and determine the molecular
mechanisms that allow pathogens to gain entry to cells in the lung;.
 
o  elucidate host factors that influence establishment and
progression of Kaposi's sarcoma in the lung.
 
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.  Investigators are encouraged to apply findings from in
vitro work to in vivo studies when this is feasible.  The initiative
is relevant to black and Hispanic minority populations who are
disproportionately affected by HIV in comparison to the total
population.
 
SPECIAL REQUIREMENTS
 
This initiative will not address mechanisms of activation of HIV in
the lung. This was the subject of another RFA, "Regulation of HIV
Activation in the Lung."  However, studies involving the influence of
HIV in either a latent or active state, pro viral components,
dysfunctional virus, or viral products, on the progression of
HIV-associated lung diseases would be appropriate.
 
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 that propose descriptive studies and do not contain
hypothesis driven studies directed at understanding the mechanisms
that influence host susceptibility to HIV-associated lung diseases
will not be acceptable. Applications that focus on these mechanisms
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 or 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,
therefore the models must be applied to the study of how host factors
affect susceptibility to HIV-associated pulmonary disease.
 
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 new
provisions that are substantially different from the 1990 policies.
 
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 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 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 March 14, 1997, 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.  Applicants
without prior R29 or R01 support are urged to identify themselves in
the letter of intent.
 
The letter of intent is to be sent or faxed to:
 
Dr. C. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and blood Institute
6701 Rockledge Drive, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3541
Email:  james_scheirer@nih.gov
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  Application kits 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 20898-7910, telephone 301-710-0267, E-mail:
asknih@odrockm1.od.nih.gov; and from Melonie Shine at the address
listed under INQUIRIES.
 
The RFA label found 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.
 
Investigators without prior R29 or R01 support are strongly
encouraged to identify their status in a cover letter.
 
This RFA is  restricted to R01 grants.  All will be awarded as
modular grants.  The modular grant concept establishes specific
modules (increments) in which direct costs may be requested and a
maximum level for requested direct cost.  Only limited budgetary
information is required in the application; a detailed budget need
not be provided.
 
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  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 FIVE 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.
 
-  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 indirect) 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.
 
Submit a signed, typewritten original of the application and three
signed, photocopies, in one package to:
 
DIVISION OF RESEARCH GRANTS
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 listed under INQUIRIES.
 
Applications must be received by April 30, 1997.  If an application
is received after that date, it will be returned to the applicant
without review. The Division of Research Grants (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.
 
o  If  an application is determined to be unresponsive to the RFA,
the principal investigator will be notified and may request that the
application be returned or sent to DRG where it will be processed in
the next available cycle as a regular grant application.
 
o  A sample budget is available upon request from Mr. Raymond
Zimmerman at the number listed under INQUIRIES.
 
REVIEW CONSIDERATIONS
 
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. As part of the initial merit review, all
applications will receive a written critique and undergo a review in
which only those applications deemed to have the highest scientific
merit of the applications under review (usually two to three times
the number of applications that the NHLBI anticipates being able to
fund under the program) will be discussed, assigned a priority score,
and receive a second level review by the National Heart, Lung, and
Blood Advisory Council.
 
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.
 
o  scientific, technical or medical significance and originality of
proposed research
 
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research
 
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research
 
o  availability of the resources necessary to perform the research
 
o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
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 and the safety of the
research environment.
 
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.
 
The anticipated date of award is September 29, 1997.
 
INQUIRIES
 
Inquiries concerning this RFA are encouraged.  Potential applicants
may request copy of sample budget pages as previously stated.  The
opportunity to clarify any issues or questions from potential
applicants is welcome.  Particularly, applicants who have not had
prior R29 or R01 support are urged to contact the NHLBI.
 
Direct requests for the sample budget pages to:
 
Melonie Shine
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
Email:  melonie_shine@nih.gov
 
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
Email:  hannah_peavy@nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Raymond L. Zimmerman
Grants Operations Branch
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:  raymond_zimmerman@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 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 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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