Full Text HL-97-010
 
ROLE OF RESPIRATORY INFECTIONS IN CHILDHOOD ASTHMA
 
NIH GUIDE, Volume 26, Number 21, June 20, 1997
 
RFA: HL-97-010
 
P.T.  34, AA

Keywords: 
  Asthma 
  Pulmonary Diseases 
  Immunology 
  Biology, Cellular 
  Biology, Molecular 

 
National Heart, Lung, and Blood Institute
National Institute of Allergy and Infectious Diseases
 
Letter of Intent Receipt Date: October 24, 1997
Application Receipt Date: December 11, 1997
 
This RFA uses "Modular Grant" and "Just-In-Time" concepts.  This full
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) and the
National Institute of Allergy and Infectious Diseases (NIAID) invite
grant applications for  research on the cellular and molecular
mechanisms by which respiratory pathogens contribute to the
development of, exacerbation of, or protection from childhood 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), "Role of Respiratory Infections in Childhood
Asthma," 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, immunology, molecular immunology, 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  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 state this 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 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 or NIAID 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 5 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 July, 1998.   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.
 
FUNDS AVAILABLE
 
It is anticipated that for fiscal year 1998, $ 2.4 million (total
costs) will be committed by the NHLBI and $0.5 million will be
committed by NIAID 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 8 new grants will be awarded under this program.  The
specific number to be funded will, however, depend on the merit and
scope of the applications received and on the availability of funds.
Direct costs will be awarded in modules of $25,000, less any overlap
or other necessary administrative adjustments.  Indirect costs will
be awarded based on the negotiated rates.  Applicants may request up
to 5 years of support.
 
RESEARCH OBJECTIVES
 
Background
 
Asthma often starts early in life; however, the characteristic
features of childhood asthma have not been clearly defined.
Important clues to the etiology of the disease are missing.  A major
issue in childhood asthma relates to the role of infections in the
development and persistence of asthma.  Clinical and epidemiologic
data suggest that viral respiratory infections and exposure to
allergens, together with the genetic background of the host, are the
most important risk factors early in life that may lead to wheezing,
prolonged alterations in airway function, and the development of
persistent asthma.  Once asthma is established, recurrent viral
infections are a major cause of asthma exacerbations in children and
adults.  Since most children who develop asthma have elevated IgE
levels and have a history of early respiratory infections, an
interplay between respiratory infections and allergens may operate in
the development of asthma.  On the other hand, it has been suggested
that the immune response to childhood tuberculosis and other
infections may actually protect against asthma and allergic disease.
Alternatively, some individuals  may be genetically predisposed to
mount strong protective immune responses on exposure to certain
infectious agents and these same individuals may be genetically
predisposed to have a reduced capacity  to develop allergic
responses. The timing, duration, and frequency of exposure to
infectious agents may affect the capacity of these agents to act as
protagonists or protectors in the development and persistence of
asthma.
 
With currently available techniques in cellular and molecular
biology, it is now possible to study the mechanisms by which some
infections trigger asthma while other infections protect against the
development of asthma. Also, studies on the role of respiratory
infections in the development of asthma may shed light on whether
respiratory infections have different functional and/or pathologic
consequences, depending on whether they occur early or late in life.
 
Research Scope:
 
This RFA is designed to address the cellular and molecular mechanisms
by which respiratory pathogens trigger or protect from the
exacerbation and/or development of asthma.  Areas of investigation
relevant to the objectives of this RFA include, but are not limited
to, the following:
 
(1) Molecular mechanisms of infection-induced airways inflammation
and remodeling.  The precise pathway(s) of pathogen-induced airways
inflammation and remodeling including the production of cytokines,
adhesion molecules, and other inflammatory mediators in airway and
nasal target tissues should be characterized. Among the specific
questions that need to be addressed are:  What are the mechanisms
underlying the a) development, b) exacerbation, and/or c) protection
from asthma by respiratory pathogens?  Are there distinct mechanisms
and biochemical pathways that distinguish respiratory infectious
agents that mediate protection from versus exacerbation of asthma?
Are there definable signal transduction and/or transcriptional
activation pathways that mediate the induction of inflammation and/or
airway wall remodeling that lead to or protect from asthma that are
specific for particular respiratory pathogens? Will inhibition of the
biochemical pathways induced by the infectious agents alter tissue
inflammation, remodeling or physiologic function ?
What are the precise pathway(s) of pathogen entry? What is the
profile of pathogen gene expression, and what mechanisms regulate its
expression? How does interaction of the pathogen with the host lead
to the development of, exacerbation of, or protection from asthma?
 
(2) The effect of pathogen-allergen interactions on sensitization,
inflammation, and airway wall remodeling.   Allergens may induce
quantitatively or qualitatively different immune and inflammatory
responses in the setting of respiratory infection. The mechanisms by
which pathogens modulate either the production of Th1 versus Th2
cytokines, or other events in sensitization, should be evaluated in
atopic and non-atopic individuals and appropriate animal models.  The
mechanisms by which interactions of pathogen with allergen modulate
pathogen-induced and/or allergen-induced inflammatory responses and
airway remodeling should also be evaluated. What interrelationships
exist between the allergic diathesis and respiratory infections?
Does the timing of an infection(s) make a difference?  Does the dose
and type of allergen presented modulate the immune/inflammatory (Th1
versus Th2) pathway?   Do differing exposures to respiratory
pathogens, and their frequency, modify the immune response?   Do
particular infections predispose to the development of a Th2-type
response leading to asthma?  Do others lead to protection from
asthma?  Do pathogen-induced airway inflammation and remodeling
influence the generation of the asthmatic diathesis?  If so, what are
the mechanisms of these pathogen-induced effects, what are the
temporal requirements for their elicitation and their regulatory
mechanisms?
 
These are examples only.  Investigators  are not limited to the
subjects mentioned above and are encouraged to submit other topics
pertinent to the objectives of the RFA.
 
While studies involving children are desirable, investigations with
young adults or with mammalian models will also be suitable for
addressing the mechanistic information sought in this RFA.
Investigators proposing studies using animal models must provide
evidence that they are relevant to both asthma and human respiratory
infections.  An application addressing fundamental aspects of
pathogen gene expression will be responsive to this RFA only if it
can demonstrate relevance to the development of, exacerbation of, or
protection from asthma.
 
Special Requirements
 
Upon initiation of the program, the NHLBI and NIAID will co-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 that
do not propose hypothesis driven studies directed at understanding
the mechanisms by which respiratory infections trigger or protect
from asthma 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.
 
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 October 24, 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
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
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev 5/95) is to be used
in applying for these grants.  Applications 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@odrockm1.od.nih.gov.
 
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.
 
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:
 
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.
 
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 Nine modules ($225,000 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.
 
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.
 
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.
 
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.
 
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
or NIAID staff if there is a possibility for an award.
 
Checklist - No "Checklist" page is required as part of the initial
application. A completed Checklist will be requested by NHLBI or
NIAID staff if there is a possibility for an award.
 
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 address listed under
LETTER OF INTENT.
 
Applications must be received by December 11, 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.
 
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.
 
A sample budget is available upon request from Ms. Tanya McCoy 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 a 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 and NIAID 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 or the National Institute of Allergy and Infectious
Diseases 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. Total 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 recommended scope of the project.
 
Review Criteria
 
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?
 
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?
 
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?
 
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)?
 
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 initial review group will also examine: the adequacy of plans to
include both genders and minorities and their subgroups as
appropriate for the scientific goals of the research and plans for
the recruitment and retention of subjects; 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 July 1, 1998.
 
INQUIRIES
 
Inquiries concerning this RFA are encouraged.  Potential applicants
may request a copy of sample budget pages.  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, Suite 10018, MSC 7952
Bethesda, Maryland 20892-7952
Telephone:  (301) 435-0202
FAX:  (301) 480-3557
E-mail: Schleges@gwgate.nhlbi.nih.gov
 
Daniel Rotrosen, M.D.
Acting Director
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases Solar Building,
Room 4A24
6003 Executive Boulevard
Bethesda, MD 20892-7640
Telephone: (301) 496-8974
FAX:  (301) 402-0175
E-mail: dr17g@nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Tanya McCoy
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Centre, Suite 7154, MSC 7926
6701 Rockledge Drive
Bethesda, MD 20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
E-mail:  mccoyt@gwgate.nhlbi.nih.gov
 
Pamela Fleming
Grants Management Branch
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases Solar Building,
Room 4C25
6003 Executive Boulevard
Bethesda, MD 20892-7610
Telephone: (301) 402-6580
FAX: (301) 480-3780
E-mail: pf49e@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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