CYTOKINES AND ADHESION IN ALLERGY AND INFLAMMATION

NIH GUIDE, Volume 22, Number 3, January 22, 1993 (inactive per NOT-HL-00-003)



PA:  PA-93-42



P.T. 34



Keywords:

  Hypersensitivity 

  Inflammation 

  Biology, Cellular 

  Biology, Molecular 

  Biochemistry, Proteins 

  Gene Cloning 



National Institute of Allergy and Infectious Diseases

National Heart, Lung and Blood Institute



PURPOSE



The Division of Allergy, Immunology, and Transplantation (DAIT) of

the National Institute of Allergy and Infectious Diseases (NIAID) and

the Division of Lung Diseases (DLD) of the National Heart, Lung, and

Blood Institute (NHLBI) invite applications for support of basic and

preclinical studies directed at determining the effects of cytokines

and adhesion molecules on immune cells involved in allergy and

inflammation.



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 Program

Announcement (PA), Cytokines and Adhesion in Allergy and

Inflammation, is related to the priority area of diabetes and chronic

disabling diseases.  Potential applicants may obtain a copy of

"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0) or

"Healthy  People 2000" (Summary Report:  Stock No. 017-001-00473-1)

through the Superintendent of Documents, Government Printing Office,

Washington, DC 20402-0325 (telephone 202-783-3238).



ELIGIBILITY REQUIREMENTS



Research grant 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 and

local governments, and eligible agencies of the Federal government.

Applications from minority individuals and women are encouraged.

Foreign institutions are not eligible to apply for the First

Independent Research Support and Transition (FIRST) award (R29).



MECHANISMS OF SUPPORT



The mechanisms of support will be the individual research project

grant (R01) and the FIRST award (R29).  Multidisciplinary approaches

that involve collaborative efforts among investigators in the fields

of basic and clinical immunology, allergy, pulmonology, biochemistry

and molecular biology are strongly encouraged.



Policies that govern research grant programs of the National

Institutes of Health (NIH) will prevail.



RESEARCH OBJECTIVES



Background



Progress in understanding the complex steps in the inflammatory

process requires a definition of the cellular interactions, of the

mechanisms of cell activation, and of the functions of the products

secreted by the activated cells.  Recent progress has resulted in

identification and cloning of adhesion molecules and cytokines, which

are important in cellular interactions and cell activation,

respectively, and in identification of several cell types that

produce cytokines.  However, the precise relationships between

adhesion molecules, cytokines and inflammation have not yet been

elucidated.



Cytokines may selectively induce expression of adhesion molecules.

For example, IL-4 induces selective expression of VCAM-1 on

endothelium, resulting in selective adherence of basophils and

eosinophils, two cell types that are prominent in chronic allergic

inflammation.  There are many other adhesion molecules and

counterreceptors on endothelium and leukocytes, and many cytokines

other than IL-4 that may influence expression of these molecules.



Cytokines also selectively induce cell activation.  IL-5 and other

cytokines (e.g., IL-3, GM-CSF) all activate eosinophils, but the

availability of these cytokines at the sites of inflammation in vivo,

and thus the relative importance of each of these cytokines, are

unknown.



Some cellular sources of cytokines are known.  IL-4 and IL-5 are

products of helper T cells, probably of the so-called TH2 subset, but

recent evidence suggests that mast cells and perhaps basophils may

also produce these cytokines, and that eosinophils may produce other

cytokines.  The relative importance of T-cell vs. non-T cell derived

cytokines has not been elucidated.



Many new cytokines have been identified and cloned in recent years,

including interleukins, interferon-~, TGF-a, colony stimulating

factors such as GM-CSF, and members of the intecrine/chemocrine

family of cytokines (such as MCAF/MCP-1 and RANTES), and many of

these have been shown to have potent effects on inflammatory cells.



Research Objectives and Scope



The NIAID and the NHLBI are interested in sponsoring research

projects to further understanding of the role of adhesion molecules

and cytokines in inflammation, especially allergic inflammation.

Areas of interest include, but are not limited to, the following:



o  Cloning the genes that encode adhesion molecules and identifying

how these genes are regulated in various microenvironments and at

various stages of inflammation.



o  Cloning the genes that encode cytokines and identifying how these

genes are regulated in various microenvironments and at various

stages of inflammation.



o  Determining the relative importance of cytokines and of different

cell sources of cytokines at various stages of inflammation in vivo.



o  Identifying the mechanisms of cell activation which result in

cytokine production.



o  Determining the biochemical and molecular characteristics of the

inflammatory cell types at various stages of inflammation.



In these proposals the use of newer techniques of molecular and

cellular biology and protein biochemistry is strongly encouraged.



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



NIH policy is that applicants for NIH clinical research grants and

cooperative agreements are required to include minorities and women

in study populations so that research findings can be of benefit to

all persons at risk of the disease, disorder or condition under

study; special emphasis must be placed on the need for inclusion of

minorities and women in studies of diseases, disorders and conditions

that disproportionately affect them.  This policy is intended to

apply to males and females of all ages.  If women or minorities are

excluded or inadequately represented in clinical research,

particularly in proposed population-based studies, a clear compelling

rationale must be provided.



The composition of the proposed study population must be described in

terms of gender and racial/ethnic group.  In addition, gender and

racial/ethnic issues should be addressed in developing a research

design and sample size appropriate for the scientific objectives of

the study.  This information must be included in the form PHS 398 in

items 1-4 of the Research Plan AND summarized in item 5, Human

Subjects.  Applicants are urged to assess carefully the feasibility

of including the broadest possible representation of minority groups.

However, NIH recognizes that it may not be feasible or appropriate in

all research projects to include representation of the full array of

United States racial/ethnic minority populations (i.e., Native

Americans (including American Indians or Alaskan Natives),

Asian/Pacific Islanders, Blacks, Hispanics).  The rationale for

studies on single minority population groups must be provided.



For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and preventive strategies), diagnosis, or treatment of

diseases, disorders or conditions, including but not limited to

clinical trials.



The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.



For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including

minorities.



If the required information is not contained within the application,

the review will be deferred until the information is provided.  Peer

reviewers will address specifically whether the research plan in the

application conforms to these policies.  If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed AND the justification for the

selected study population is inadequate, it will be considered a

scientific weakness or deficiency in the study design and will be

reflected in assigning the priority score to the application.



All applications for clinical research submitted to NIH are required

to address these policies.  NIH funding components will not award

grants or cooperative agreements that do not comply with these

policies.



APPLICATION PROCEDURES



Applicants are to use the research grant application form PHS 398

(rev. 9/91).  For purposes of identification and processing, check

yes on item 2a of the face page and enter the PA number and title:

"PA-93-42:  Cytokines and Adhesion in Allergy and Inflammation."

Applications will be accepted in accordance with the standard

submission dates for new applications:  February 1, June 1, and

October 1.



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.



Application kits are available at most institutional offices of

sponsored research and may be obtained from the Office of Grants

Inquiries, Division of Research Grants, National Institutes of

Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone

(301) 496-7441.



The completed original signed application and five legible copies

must be sent or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



For FIRST award (R29) applications, three reference letters (in

sealed envelopes) must be attached to the face page of the original

application and submitted with the application.  Failure to provide

the three reference letters will result in return of the application

to the investigator.



REVIEW PROCEDURES



Applications will be assigned on the basis of established PHS

referral guidelines.  Applications will be reviewed for scientific

and technical merit by study sections of the Division of Research

Grants, NIH, in accordance with the standard NIH peer review

procedures.  Following scientific-technical review, the applications

will receive a second-level review by an appropriate national

advisory council or board.



AWARD CRITERIA



Applications will compete for available funds with all other approved

applications.  The following will be considered in making funding

decisions: quality of the proposed project as determined by peer

review, availability of funds, and program balance among research

areas of the announcement.



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.



Direct inquiries regarding programmatic issues to:



Eugene M. Zimmerman, Ph.D.

Chief, Allergic Mechanisms Section

National Institute of Allergy and Infectious Diseases

Solar Building, Room 4A24

Bethesda, MD  20892

Telephone:  (301) 496-8973

FAX:  (301) 402-2571



Susan P. Banks-Schlegel, Ph.D.

Division of Lung Diseases

National Heart, Lung and Blood Institute

Westwood Building, Room 6A15

Bethesda, MD  20892

Telephone:  (301) 496-7332

FAX:  (301) 496-9886



Direct inquiries regarding fiscal matters to:



Mr. Jeffrey Carow

Immunology Grants Management Section

National Institute of Allergy and Infectious Diseases

Solar Building, Room 4B29

Bethesda, MD  20892

Telephone:  (301) 496-7075



Tanya McCoy

Division of Extramural Affairs

National Heart, Lung and Blood Institute

Westwood Building, Room 4A17A

Bethesda, MD  20892

Telephone:  (301) 496-4970



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic

Assistance, No. 93.855 and No. 93.838.  Grants are awarded under the

authority of the Public Health Service Act, Section 301 (42 USC 241)

and 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, most specifically at 42 CFR Part 52

and 45 CFR Part 74.  This program is not subject to the

intergovernmental review requirements of Executive Order 12372 or

Health Systems Agency review.



.

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