Release Date:  October 15, 1999

RFA: HL-00-005  

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date: January 21, 2000
Application Receipt Date: February 25, 2000



Genome-wide screening has been useful in determining chromosomal regions 
containing asthma and asthma-associated susceptibility genes.  The National 
Heart, Lung, and Blood Institute (NHLBI) invites research grant applications to 
employ positional candidate gene approaches to identify the gene or genes in a 
particular region(s) that are linked to asthma or asthma-associated phenotypes, 
using traditional and novel genomic technologies.


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), 
"Positional Candidate Gene Approaches in Asthma Gene Discovery," is related to 
one or more of the priority areas.  Potential applicants may obtain a copy of 
"Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000.


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.  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. Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 


This RFA will use the National Institutes of Health (NIH) research project grant 
(R01) award mechanism.  Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.  The 
total project period for an application that is received in response to this RFA 
may not exceed five years.  This RFA is a one-time solicitation.  Future 
unsolicited competing continuation applications will compete with all 
investigator-initiated applications and be reviewed according to the customary 
peer review procedures.  The anticipated award date is September 29, 2000.

Specific application instructions have been modified to reflect "MODULAR GRANT" 
and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and 
detailed instructions and information on Modular Grant applications can be found 
at https://grants.nih.gov/grants/funding/modular/modular.htm.  For this RFA, 
funds must be requested in $25,000 direct cost modules and a maximum of 11 
modules ($275,000 direct costs) per year may be requested.  An R01 grant 
application may include research activities that involve institutions other than 
the sponsoring organization, creating a consortium effort.  Under the "Funds 
Available" section, the accommodation being allowed for investigators utilizing 
consortium arrangements to accomplish the goals of this RFA is described.

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 either from the GCRC program director or principal investigator should 
be included with the application.


The NHLBI intends to commit approximately $3,200,000 total costs in FY 2000 to 
fund up to eight new grants in response to this RFA.  An application may request 
a project period of up to five years and a budget for direct costs of up to 
$275,000 per year.  An R01 grant application may include research activities 
that involve institutions other than the sponsoring organization, creating a 
consortium effort.  The consortium costs may possibly be included in the 
$275,000 cost limit.  However, up to three additional modules ($75,000) over the 
direct cost limit ($275,000) will be allowed to cover consortium arrangements.  
These additional modules for the consortium include both Direct and Facilities 
and Administrative (F&A) costs and may only be requested by those applicants who 
are planning to involve consortium arrangements.  Those applicants who do not 
involve any consortium activities may not exceed the direct cost maximum 
($275,000).  Because the nature and scope of the research proposed may vary, it 
is anticipated that the size of each award will also vary.  Although the 
financial plans of the NHLBI provide support for this program, awards pursuant 
to this RFA are contingent upon the availability of funds and the receipt of a 
sufficient number of applications of appropriate scientific and technical merit.



Asthma is a genetically complex disease.  Understanding the genetic mechanisms 
responsible for asthma and allergy has widespread public health significance 
since it may lead to a better understanding of the pathogenesis of asthma, as 
well as improved preventive measures and new therapeutic approaches.

Despite the complexity of asthma, considerable progress has been made in 
determining the regions of  the genome likely to contain susceptibility genes 
for asthma and asthma-associated phenotypes.  Several genome-wide screening 
studies showed evidence of linkage of asthma and asthma-associated traits to 
multiple regions of the genome, including chromosomes 5, 6, 11, 12, 13, and 14.  
Although many of these regions are shared within different study populations, 
some linkages appear to be unique to specific ethnic groups. Now the difficult 
process of finding these genes and their relevant mutations must be undertaken.  
The number of biologically plausible candidate genes that might be involved in 
the determination of asthma and asthma-associated traits in these regions is 
very large, likely involving hundreds of genes within each of these linkage 
regions.  In addition, it has recently become clear that the haplotype of any 
given gene may be as important, if not more so, than a single polymorphism in a 
gene.  Association studies in candidate gene and haplotype sharing offer 
valuable approaches to facilitate efforts to find the genes, and provide 
important insights into fine mapping and gene localization endeavors.

Although the study of complex genetic diseases is in its infancy, the near 
completion of the human genome project and the development of high-throughput 
technologies such as "gene chip" and streamlined SNP (single nucleotide 
polymorphism) analyses should greatly facilitate the search for genes linked to 
the various chromosomal regions.  Identification of asthma susceptibility genes 
will aid in deciphering the molecular mechanisms predisposing to asthma and 
should lead to development of safer and more effective therapies.

Research Scope

This initiative is intended to solicit applications to identify the gene or 
genes in a particular region that are linked to asthma or asthma-associated 
phenotypes (using state-of-the-art approaches including, but not limited to, 
positional candidate cloning, positional cloning to narrow the region, computer 
cloning, and genomic technologies), to characterize the allelic variants of the 
gene(s) identified, and to demonstrate that the variation in the gene(s) is 
disease-associated.  Applicants must be able to demonstrate the availability of 
well-characterized families with asthma and/or well-defined genetic animal 
models of asthma in whom  linkage has been demonstrated to particular 
chromosomal regions to asthma or an asthma-associated phenotype, such as 
bronchial hyperresponsiveness, atopy, or eosinophilia.

Some research topics that will be responsive to this program are listed below.  
These are only examples; applicants are encouraged to propose other topics that 
address the overall goals of this initiative. 

The following are examples of research areas relevant to the objectives of this 

o  Asthma and asthma-associated traits have been linked to multiple regions of 
the genome.  Studies are now needed to identify specific polymorphisms in 
candidate genes that lie within these linkage regions.  Although it will likely 
be prudent to begin examining intuitive candidates within linkage regions, this 
approach can greatly bias the results and potentially lead to exclusion of 
important genes.  Thus investigators should consider combining new high 
throughput technologies such as "gene chip" approaches and rapid SNP analyses 
with the more traditional approaches.  Recent advances in molecular techniques 
such as "gene chip technology" have provided considerable power and speed in 
identification of differentially expressed genes.  Functional genomic approaches 
(using cDNA and oligonucleotide arrays) to identify differentially expressed 
genes, combined with classic genetic analysis and positional candidate 
approaches, can significantly enhance gene discovery efforts. 

o Recently, specific haplotypes of the IL-4Ra gene have been shown to be more 
strongly associated with asthma traits than are single polymorphisms within this 
gene.  This may also be the case for many of the candidate genes within the 
currently identified linkage regions.  Thus, studies designed to assess the 
contribution of haplotypes within these regions are needed.

o  In complex genetic diseases, interactions of multiple genes likely result in 
expression of specific disease traits. Once polymorphisms within each linkage 
region are identified, efforts should be directed at assessing gene-gene 

o  Linkages identified to date only account for a small fraction of the 
variability in the expression of asthma suggesting that gene-environment 
interactions may play a significant role in predisposition to this disease.  
Thus, studies to access these gene-environment interactions are also needed. 

o A variety of animal models of asthma have advanced our understanding of the 
pathogenesis of asthma.  As genetic studies of animal models of other complex 
diseases, such as obesity, have yielded important insight into the mechanisms 
underlying these disease states, it is likely that they will be equally useful 
in the study of asthma.  Numerous inbred murine strains, with well-defined 
genomes that exhibit a high degree of homology with the human genome, have 
considerable potential to provide insights into the pathogenesis of asthma.  
Thus, studies that explore the genetic basis of animal models of asthma are 

o The molecular pathways that explain the basis for the association of a 
particular gene(s) with asthma or asthma-associated phenotypes need to be 
elucidated to provide further insights into the pathogenesis of asthma.  In 
addition to human studies, in vitro and/or animal studies could be used to 
explore the functional contribution of various candidate genes to asthma or 
asthma-associated phenotypes.  



Applications that propose positional candidate gene approaches for asthma gene 
discovery that cannot demonstrate the availability of well-characterized 
families with asthma and/or well-defined animal models of asthma in whom linkage 
has been demonstrated to particular chromosomal regions to asthma or an asthma-
associated phenotype, such as bronchial hyperresponsiveness, atopy, serum IgE, 
eosinophilia, or other potential biomarkers, will not be responsive to the RFA.  
Studies of the genetic basis of animal models of asthma are responsive to this 
RFA.  However, applicants who propose to conduct genetic studies using animal 
models must demonstrate their usefulness in gaining insights into the genetics 
of human asthma. Companion studies designed to extend and validate findings in 
human asthma are particularly encouraged. Human studies are especially 
solicited.  Large clinical studies or epidemiologic studies are not within the 
scope of this RFA. 

Upon initiation of the program, the NHLBI will sponsor periodic meetings to 
encourage exchange of information among investigators who participate in this 
program.  This is especially critical if more than one group focuses on the same 
chromosomal region to avoid unnecessary duplication and to expedite asthma gene 
discovery efforts.  Travel funds should be included in the modules for two 
people (the Principal Investigator and one co-investigator from the grant) to 
attend a one day meeting two times each year, most likely to be held in 
Bethesda, Maryland. Applicants should also include a statement in their 
application indicating their willingness to participate in these meetings and to 
interact openly with other study participants in sharing genetic 
approaches/strategies and findings among awardees so as to provide the greatest 
promise for scientific advances from the approved research scope of the awards..


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).

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, Volume 23, 
Number 11, March 18, 1994, available on the web at: 


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

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects" that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 

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


Prospective applicants are asked to submit 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 mailed to Dr. C. James Scheirer at the 
address listed under INQUIRIES.


The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants, with the modifications noted below.  These forms are 
available at most institutional offices of sponsored research and from the 
Division of Extramural Outreach and Information Resources, National Institutes 
of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 
301/710-0267, email: GrantsInfo@nih.gov.

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 the applicant to submit certain information only when there is a 
possibility for an award.  It is anticipated that these changes will reduce the 
administrative burden for the applicants, reviewers, and Institute staff. 


Modular Grant applications will request direct costs in $25,000 modules, up to
a maximum total direct cost request of $275,000 per year.  An R01 grant 
application may include research activities that involve institutions other than 
the sponsoring organization, creating a consortium effort.  The consortium costs 
may possibly be included in the $275,000 cost limit.  However, up to three 
additional modules ($75,000) over the direct cost limit ($275,000) will be 
allowed to cover consortium arrangements.  These additional modules for the 
consortium include both Direct and Facilities and Administrative (F&A) costs and 
may only be requested by those applicants who are planning to involve consortium 
arrangements.  Those applicants who do not involve any consortium activities may 
not exceed the direct cost maximum ($275,000). 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:  Items 7a and 7b should be completed, indicating Direct Costs
(in $25,000 increments up to a maximum of $275,000 unless including consortium 
costs for which the program guidelines were explained earlier in the RFA 
document under Mechanisms of Support) and Total Costs [Modular Total Direct plus 
F&A costs] for the initial budget period. Items 8a and 8b should be completed 
indicating the Direct and Total Costs for the entire proposed period of support. 

of the PHS 398.  It is not required nor will it be accepted at the time of 

categorical budget table on Form page 5 of the PHS 398.  It is not required and 
will not be accepted with the application. 

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
(See https://grants.nih.gov/grants/funding/modular/modular.htm for sample pages).  
At the top of the page, enter the total direct costs requested for each year.  
This is not a Form page.

o Under Personnel, list key project personnel, including their names, percent of 
effort and roles on the project.  No individual salary information should be 
provided.  However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual Costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the nearest 
$1,000.  For this RFA. the consortium costs may possibly be included in the 
$275,000 cost limit.  However, up to three additional modules ($75,000) over the 
direct cost limit ($275,000) will be allowed to cover consortium arrangements.  
These additional modules for the consortium include both Direct and Facilities 
and Administrative (F&A) costs and may only be requested by those applicants who 
are planning to involve consortium arrangements.  Those applicants who do not 
involve any consortium activities may not exceed the direct cost maximum 
($275,000). List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of key personnel, 
and the role on the project.  Indicate whether the collaborative institution is 
foreign or domestic.  The total cost for a consortium/contractual arrangement is 
included in the overall requested modular direct cost amount.  Include the 
Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o  BIOGRAPHICAL SKETCH - The biographical sketch provides information used by 
reviewers in the assessment of each individual's qualifications for a specific 
role in the proposed project, as well as to evaluate the overall qualifications 
of the research team.  A biographical sketch is required for all key personnel, 
following the modified instructions below.  No more than three pages may be used 
for each person.  A sample biographical sketch may be viewed at: 

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on research 
projects ongoing or completed during the last three years;
- List selected peer-reviewed publications, with full citation;

o  CHECKLIST - This page should be completed and submitted with the application.  
If the F&A rate agreement has been established, indicate the type of agreement 
and the date.  All appropriate exclusions must be applied in the calculation of 
the F&A costs for the initial budget period and all future budget years.

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.

The RFA label found in the PHS 398 (rev. 4/98) 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 (Positional 
Candidate Gene Approaches in Asthma Gene Discovery) and number (HL-00-005) must 
be typed on line 2 of the face page of the application form and the YES box must 
be marked.  

The sample RFA label available at:
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to 
allow for this change.  Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the 
checklist, and three signed, photocopies, in one package to:

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.


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.


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

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NHLBI in accordance with the review criteria stated below.  As part of the 
initial merit review, a process will be used by the initial review group in 
which applications receive a written critique and undergo a process in which 
only those applications deemed to have the highest scientific merit, generally 
the top half of the applications under review, will be discussed, assigned a 
priority score, and receive a second level review by the National Heart, Lung, 
and Blood Advisory Council (NHLBAC).

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 comments, reviewers will be asked to discuss the following aspects of 
the application in order to judge the likelihood that the proposed research will 
have a substantial impact on the pursuit of these goals.  Each of these criteria 
will be addressed and considered in assigning the overall score, weighting them 
as appropriate for each application.  Note that the application does not need to 
be strong in all categories to be judged to have major scientific impact and 
thus deserve a high priority score. For example, an investigator may propose to 
carry out important work that by its nature is not innovative but is essential 
to move a field forward.

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

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 to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

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

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

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

The initial review group will also examine the provisions for the protection of 
human subjects and the safety of the research environment.

The personnel category will be reviewed for appropriate staffing based on the 
requested percent effort and justification provided.  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 


Letter of Intent Receipt Date:                            January 21, 2000
Application Receipt Date:                                 February 25, 2000
Date of Initial Review:                                   June/July 2000
Review by NHLB Advisory Council:                  		September 2000 
Anticipated Award Date:                                    September 2000


Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)

o Availability of funds

o Programmatic priorities and program balance


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:

Susan Banks-Schlegel, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room10018, MSC 7952
Bethesda, Maryland 20892-7952

Telephone:  (301) 435-0202
FAX:  (301) 480-3557
E-mail: SchlegeS@ nih.gov

Direct inquiries regarding review matters to:
C. James Scheirer, Ph.D..
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, Maryland 20892-7924

Telephone: (301) 435-0266
FAX: (301) 480-3541
E-mail: js110j@nih.gov

Direct inquiries regarding fiscal matters to:
Raymond L. Zimmerman
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7154, MSC 7926
Bethesda, MD 20892-7926

Telephone:  (301) 435-0171
FAX:  (301) 480-3310
E-mail: ZimmermR@ nih.gov 


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, as 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 and 92.  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 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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