ORIGINS OF ASTHMA IN EARLY LIFE

NIH GUIDE, Volume 26, Number 39, December 5, 1997

RFA:  HL-98-005

P.T.

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  February 2, 1998
Application Receipt Date:  March 17, 1998

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 grant applications
for research on the maternal, fetal, and early childhood risk factors for the
onset of asthma and the cellular and molecular mechanisms that cause them.  The
overall goals of this initiative are to define how genetic and environmental
factors interact in the developing lung and lead to the onset of asthma.  The
initiative is aimed at defining the interrelationships between maternal factors
and early life events that influence lung and immune system development and the
expression of the inflammatory and structural changes in the airways that are
characteristic of asthma.  The research will pursue the mechanisms by which
specific risk factors could result in the condition of asthma.

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),
"Origins of Asthma in Early Life," is related to the priority area of Chronic
Disabling Conditions.  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

Among the disciplines and expertise that may be appropriate for this research
program are microbiology, virology, molecular biology, cell biology,
developmental biology, immunology, molecular immunology, immunologic-
epidemiology, infectious diseases, allergy, asthma, genetics, pulmonary medicine,
pulmonary physiology, and pediatrics.

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.  However, 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.

For this RFA, funds must be requested in $25,000 direct cost modules and a
maximum of nine modules ($225,000 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 4 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 30, 1998.

FUNDS AVAILABLE

It is anticipated that for fiscal year 1998, $2.4 million (total costs) will be
committed by the NHLBI to fund applications submitted in response to this RFA. 
Award of grants pursuant to this RFA is contingent upon availability of such
funds for this purpose.  It is anticipated that approximately 7 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 (indirect) costs will be awarded based on the negotiated rates. 
Applicants may request up to 4 years of support.

Although not co-sponsoring this RFA, other Institutes have an interest in the
research area discussed in this RFA.  Applications submitted to and not selected
for funding by the NHLBI in response to this RFA may be considered for funding
by the National Institute of Allergy and Infectious Diseases or the National
Institute of Environmental Health Sciences, according to referral guidelines.

RESEARCH OBJECTIVES

Background

The last two decades have witnessed a progressive increase in the prevalence of
asthma.  Family clustering of asthma and allergy suggests a genetic basis, but
since the genetic background of the populations has not changed significantly
over this period, it is most likely  that the rising trend relates to
environmental factors interacting with susceptibility genes. A major step forward
in our understanding of asthma will occur only when more is known of these gene-
environmental interactions and how they manifest in this disease of the airways. 
Defining how genetic and environmental factors interact to predispose certain
individuals to develop asthma holds the key for prevention strategies for asthma.

Studies have strongly suggested the importance of the immune system in
orchestrating many of the events critical to the development of asthma. There are
alternative hypotheses regarding the development of the Th2 (T helper 2) immune
pathway leading to the onset of asthma.  One hypothesis suggests that early
exposure to certain infections (e.g. measles, tuberculosis, certain respiratory
viruses) enhances the Th1 response and thus protects against the development of
the Th2 response.  Another hypothesis suggests that  individuals may be
predisposed to vigorous Th1 responses, on the basis of genetics, in utero events
or other processes, and thus respond differently to environmental exposures and
have less prominent Th2 response later in life.  It has also been postulated that
an over exuberant Th2 response (e.g. resulting from a parasitic infection) is
protective against the development of allergy, although the mechanism is unknown.

Immune responses characteristic of allergen sensitization can be seen as early
as 8-10 weeks of gestation.  For example, fetal T cells are able to produce
proliferative responses to a variety of allergens, suggesting that there may be
a strong maternal influence on the fetal immune response that may be important
in the development of asthma.

Epidemiologic studies have suggested that cigarette smoking in pregnancy, young
maternal age, and maternal diet (e.g. deficiencies in polyunsaturated fatty acid
content and/or antioxidants) are risk factors for the development of asthma. 
Further study is essential to confirm these potential maternal risk factors and
identify the underlying mechanisms.  How these factors influence maternal
programming of the fetal immune response and lead to the development of asthma
in the offspring needs to be explored.

Furthermore, studies of infants and young children demonstrate that environmental
exposures during the first 3 years of life are also important in determining the
onset, persistence, and severity of asthma.  Aeroallergen load and adjuvant
factors (e.g. smoking or respiratory infection) can enhance or inhibit the Th2
mediated allergic response.  Diet in early childhood has been shown to influence
the expression of wheezing illness in children.

The relative importance of maternal, fetal, or early life events, or possibly a
combination of these factors, in the development of asthma is uncertain and needs
to be explicated.

Research Scope

This RFA is designed to foster research that focuses on elucidating the maternal
and early life risk factors for onset of asthma and the underlying cellular and
molecular mechanisms.

Basic research, clinical and immunological-epidemiological investigations with
women of childbearing age, infants and young children, human tissue, and/or
mammalian models of disease will be suitable for addressing the mechanistic
information sought in this announcement.  Areas of investigation relevant to the
objectives of this RFA include, but are not limited to:

The role of early life Th1 vs. Th2 responses in the onset of asthma. Studies
designed to elucidate the temporal and mechanistic roles of the Th2 response in
the onset of asthma are needed.  Among the questions that need to be addressed
are: Does the placenta influence the balance between Th1 and Th2 responses in the
developing fetus?  What is the site of allergen specific T cell sensitization in
utero?  Are there factors in the amniotic fluid that influence the development
of antigen presenting cells  in the lung?  What is the role of the dendritic cell
?  Do maternal dietary factors influence the fetal thymic control of T cell
switching in babies born of atopic mothers?  By what mechanisms does maternal
smoking influence selection of fetal T cell responses and IgE production?  Does
immune deviation operate in the development of asthma as postulated?  At what
point in the development of the immune system and the development of the lung
does an immune deviation take place?  What makes the lung the target organ: is
the lung the initiator or the recipient of the immune deviation that leads to
asthma?

The role of environmental exposures during critical periods of the developing
lung and immune system.  Studies are needed to determine if there is particularly
vulnerable point in the development of the lung and immune system (a "pre-asthma
state") in which exposures bring about asthma in genetically predisposed infants
and young children. Epidemiological studies indicate that sensitization to
allergens appears early in life for asthma but not necessarily for other allergic
disease, and that there is no one unique allergen solely responsible for
sensitization (i.e. many different allergens are implicated in the development
of asthma; removal of one type of allergen does not appear to preclude
sensitization to another type of allergen).  Does the type and extent of allergen
exposure during the first 1-3 years of life impact on allergic sensitization of
the airways?  Is it the size of the allergen or the cumulative allergen load that
is important in determining sensitization that leads to asthma?  Is allergen
deposition in the lung a systemic, cellular response or a local response to a
local antigen presentation?  Why does the immune reaction occur only in the lung?

What is the influence of passive smoking and indoor air pollutants as adjuvants
for allergen sensitization and factors impairing airway growth and function?

What is the effect of diet, particularly anti-oxidant vitamins (C,E, and A),
omega-3 fatty acids, and excess macro-nutrients (such as carbohydrate, fat and
protein) on programming the immune response and onset of asthma in young
children?

Does the timing of the environmental exposure make a difference in the onset of
the asthma?  What mechanisms explain this?

Are there factors other than immunologic mechanisms that affect the developing
lung and the early onset of airway hyperreactivity?

These are examples only. Investigators are not limited to the subjects mentioned
above, nor is a single grant application expected to respond to all questions. 
Investigators are encouraged to submit other topics pertinent to the objectives
of the RFA.

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 that are primarily descriptive or epidemiological will not be
acceptable unless they are directed at understanding the mechanisms by which risk
factors cause the onset of asthma.  Although studies in human subjects are
strongly encouraged, large clinical studies are not within the scope of this RFA.
For example, large clinical trials examining the impact of allergen avoidance on
the incidence of asthma will not be acceptable. Demonstration and education
research applications will not be considered responsive to this RFA.  Applicants
who propose to test hypotheses in animal or in vitro models must provide a strong
rationale for relevance to asthma in the human host.  This program will not
support studies directed at development of animal models alone.  Applications
that were submitted in response to RFA HL-91-010 "Role of Respiratory Infections
in Childhood Asthma" may not be simultaneously submitted to this RFA.

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.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 2, 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 NIH 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:

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

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev 5/95) is to be used in applying
for these grants and the modified instructions in this RFA should be followed. 
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 20892-7910, telephone 301-435-0714, Email: ASKNIH@od.nih.gov

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, to identify the application
as a response to this RFA, check "YES" in item 2 of page 1 of the application and
enter the title "Origins of Asthma In Early Life, HL-98-005."

Sample budgets and justification page will be provided upon request from Mr.
Raymond Zimmerman at the number listed under INQUIRIES.

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

BUDGET INSTRUCTIONS

The total direct costs must be requested in accordance with the program
guidelines and modifications made to the standard PHS 398 application
instructions as 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 facilities
and administrative 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 10 modules
($250,000 direct costs) per year may be requested and each applicant may request
up to four years of support for this RFA.  Equipment is included in the budget
limitation.  If an application includes research activities that involve
institutions other than the application institution, the activity is considered
a consortium effort.  The total cost (direct costs and facilities and
administrative) of consortium arrangements are included in the budget limitation.

If there is a possibility of an award, applicants will be asked to confirm that
the salary budgeted for any one project member does not exceed an annual rate cap
of $125,000 per year in any budget period.

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 required to
accomplish the proposed research changes 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 their 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 the
budget limitations.  No specific costs for items or categories should be shown.
-Separate justification should be provided for the use of grant funds to support
a scientific element of the project outside the United States or its territories
including but not limited to travel, surveying, and data or sample collection.

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 plus
facilities and administrative costs) 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 the actual direct and facilities and administrative costs for all years
of the consortium.  Please note that total subcontract costs are not to be
calculated in $25,000 modules.  However, when subcontract funds are added to the
parent grant budget, the total cost of the consortium or contract must be
included in the number of $25,000 modules requested.

o  BIOGRAPHICAL SKETCH
-Biographical sketches are required for 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 the staff of NHLBI or collaborating Institutes if there is a possibility for
an award.

o  CHECKLIST
No "Checklist" page is required as part of the initial application.  A completed
Checklist including a breakdown of facilities and administrative cost
calculations (rate, base, and base exclusions) will be requested by the staff of
NHLBI or collaborating Institutes 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:

CENTER FOR SCIENTIFIC REVIEW (formerly 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 address listed under INQUIRIES.  Applications
must be received by March 17, 1998.  If an application is received after this
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 also not accept any
application that is essentially the same as one already reviewed.  This does not
preclude the submission of substantial revisions of applications already
reviewed, but such applications must include an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and for
responsiveness to this RFA by the 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 Division of Extramural Affairs, NHLBI.

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 anticipate 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 following criteria will be considered when assessing the scientific and
technical merit of a research grant application:

(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 key personnel?

(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?

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.

AWARD CRITERIA

The anticipated date of award is September 30, 1998.  Factors that will be taken
into consideration in making awards include the scientific merit of the proposed
program as determined by peer review, the availability of funds, relevance to the
scientific programs of the NHLBI, and overall programmatic balance and
priorities.  Subject to the availability of necessary funds and consonant with
the priorities of this RFA, the NHLBI will provide funds for a project period up
to four years.

INQUIRIES

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:

Virginia S. Taggart, M.P.H.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0202
FAX:  (301) 480-3557
Email:  vt10s@nih.gov

Direct inquiries regarding fiscal matters to:

Ray 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

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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