MEMBRANE PROPERTIES: EXPLORATION OF SPERM/MICROBE SUSCEPTIBILITY
Release Date: February 24, 2000
PA NUMBER: PAS-00-067
National Institute of Child Health and Human Development
THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.
PURPOSE
The purpose of this program announcement is to encourage research to explore
the similarities between membranes of spermatozoa and pathogens, and the
properties that contribute to differential fusibility of membranes at the
molecular level. The results may have implications for design of spermicidal
microbicides for contraception and prevention of HIV and other viral or
bacterial infections.
The goal of this initiative is to discover membrane properties that
spermatozoa share with a variety of pathogens, including HIV, that render them
susceptible to attack by naturally occurring and synthetic antimicrobial
peptides and other non-surfactant compounds. It has been hypothesized that
these properties or components are related to spermatozoa and pathogens having
externally fusible membranes, and that such properties are lacking in
membranes that are resistant to external fusion. Research supported under
this announcement would identify the components that cause spermatozoa, HIV,
and other pathogens to be targets of antimicrobial agents that spare
epithelial cells. Such information would be useful in the design of
spermicides with microbicidal activity. Additionally, research to assess, at
a molecular level, the process involved in cell fusion and the properties of
membranes that aid in viral adsorption is encouraged. The intent is to
develop a better understanding of the basic science of membrane fusion that
could lead to more targeted drug design for antiviral/antibacterial
spermicidal compounds.
HEALTHY PEOPLE 2010
The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2010," a PHS-led national
activity for setting priority areas. This Program Announcement (PA) is related
to one or more of the priority areas. Potential applicants may obtain "Healthy
People 2010" at http://odphp.osophs.dhhs.gov/pubs/hp2000.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and 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.
MECHANISM OF SUPPORT
This PA will use the National Institutes of Health (NIH) research project
grant (R01) and small grant (R03) award mechanisms. 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 submitted in
response to this PA may not exceed five years for an R01 and two years for an
R03.
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
http://grants.nih.gov/grants/funding/modular/modular.htm.
FUNDS AVAILABLE
The NICHD intends to commit up to a total of $1 million per year in total
costs (direct plus facilities and administrative [F&A] costs) to fund new
grants in response to this PA. Awards are contingent upon the availability of
funds and the receipt of a sufficient number of meritorious applications. This
PA will remain active for three years, through the June 2003 application
receipt date.
RESEARCH OBJECTIVES
Background
Sexually transmitted diseases (STDs) are a major health problem throughout the
world and human immunodeficiency virus type-1 (HIV-1) infection is spreading
most rapidly due to heterosexual transmission to women. Thus, there is a need
for more woman-controlled methods for prevention of infection with HIV and
other STDs. Microbicides offer a potential alternative to physical barrier
methods for prevention of HIV transmission. Development of effective
microbicidal agents has been hindered by a variety of factors, including the
lack of reliable animal models and constraints experienced in clinical
testing. The challenge is to generate agents that target pathogens without
damaging healthy tissue. Currently marketed spermicides are surfactants that
dissolve cell membranes indiscriminately, affecting pathogens, sperm, and
epithelial cells alike, often irritating or damaging vaginal epithelium. The
ideal spermicidal microbicide would not affect epithelial cells while killing
spermatozoa and pathogens.
There may be similarities among spermatozoa, bacteria, and enveloped viruses
that can be used to advantage. All have membranes that are capable of
external membrane fusion, membrane fusion is an integral process for both
fertilization and infection of cells, i.e., the sperm head is designed to fuse
with the egg during fertilization, while bacteria and enveloped viruses fuse
with somatic cell membranes. Additionally, infection of cells by some viruses
alters the nature of the infected cell membrane, resulting in fusion between
fusion-resistant cell types. In humans, for example, epithelial and other
non-germ cells normally do not fuse with each other, although infection with
some strains of syncytium-inducing viruses (including HIV), as well as other
viruses, can cause cell fusion under one set of circumstances and not under
others. Since the mechanism by which cell membranes are differentially
susceptible to external fusion is not well understood, research on models of
membrane fusion may offer opportunities to identify the critical components
involved in the process. Additionally, research to identify the factors
involving entry of the virus into cells, including the process of cell fusion,
is needed.
Theoretically, a substance that attacks cells with externally fusible
membranes as well as enveloped viruses, while sparing cells with fusion-
resistant membranes, could be an excellent spermicide/microbicide. Similarly,
a compound that prevents viral fusion could be an effective antiviral agent.
Thus, an understanding of the fusion mechanism could lead to a more rational
drug design that is specifically directed toward fusion-enabling elements in
cell, viral, and bacterial membranes.
Scope of Research
Applications are solicited for research designed to elucidate properties that
account for differential fusibility of membranes. Factors that are common to
membranes of spermatozoa and pathogenic organisms, but are absent in somatic
cell membranes, are of special interest, because identification of such
factors may lead to effective drug development. Possible candidates for such
factors include glycosaminoglycans, lipid content, protein receptors, or other
components. Additionally, factors that transform fusion-resistant membranes
into fusible membranes, and mechanisms by which this occurs, could be
explored. Research to develop model systems for sperm-egg, bacteria-cell,
and virus-cell fusion may be supported within the scope of this program.
Appropriate topics for investigation include, but are not limited to:
o Membrane properties that spermatozoa share with a variety of pathogens,
including HIV, that render these cells susceptible to attack by antimicrobial
peptides or other non-surfactant compounds.
o Factors that are common to membranes of spermatozoa and pathogens, but are
absent in somatic cell membranes.
o Differences between fusion-capable and fusion-resistant membranes in terms
of glycosaminoglycans, lipid content, protein receptors, etc.
o Properties of membranes that aid in viral or bacterial adsorption.
o Factors, in addition to known fusion proteins, that transform fusion-
resistant membranes into fusion-competent membranes, and mechanisms by which
this transformation occurs.
o Membrane properties that determine cell type dependence on induction of
syncytia formation as a result of infection.
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 are 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 read the
NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research, 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, and available at:
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of 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/or 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," published in the NIH Guide for Grants and
Contracts, March 6, 1998, and available at:
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.
Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff also may provide additional relevant
information concerning the policy.
URLS in NIH GRANT APPLICATIONS OR APPENDICES
All applications and proposals for NIH funding must be self-contained within
specified page limitations. Unless otherwise specified in an NIH
solicitation, Internet addresses (URLs) should not be used to provide
information necessary to the review because reviewers are under no obligation
to view the Internet sites. Reviewers are cautioned that their anonymity may
be compromised when they directly access an Internet site.
APPLICATION PROCEDURES
Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard AIDS-related application receipt
dates as indicated in the application kit. Application kits are available at
most institutional offices of sponsored research, on the Internet at
http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the Division
of Extramural Outreach and Information Resources, National Institutes of
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301-435-0714, E-mail: GrantsInfo@nih.gov.
An applicant planning to submit an investigator-initiated new (Type 1),
competing continuation (Type 2), competing supplement (Type 3), or any
amended/revised version of the preceding grant application types, requesting
$500,000 or more in direct costs for any year are advised that he or she must
contact the Institute or Center (IC) program staff before submitting the
application, i.e., as plans for the study are being developed. Furthermore,
the applicant must obtain agreement from the IC staff that the institute will
accept the application for consideration for award. Finally, the applicant
must identify, in a cover letter sent with the application, the staff member
and Institute or Center who agreed to accept assignment of the application.
This policy requires an applicant to obtain agreement for acceptance of both
any such application and any such subsequent amendment. Refer to the NIH
Guide for Grants and Contracts, March 20, 1998 at
http://grants.nih.gov/grants/guide/notice-files/not98-030.html.
Special Instructions for Modular Grant Application Procedures
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, reviewers, and
Institute staff. The research grant application form PHS 398 (rev. 4/98) is
to be used in applying for these grants, with the modifications noted below.
Modular Grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $250,000 per year. (Applications that request
more than $250,000 direct costs in any year must follow the traditional PHS
398 application instructions.) The total direct costs must be requested in
accordance with the program guidelines and the modifications made to the
standard PHS 398 application instructions described below:
o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative (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.
o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4
of the PHS 398. It is not required and will not be accepted with the
application.
o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the
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
page. (See http://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.
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 F & A) for each year, each rounded to the nearest $1,000. 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 collaborating 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 instructions below. No more than three pages
may be used for each person. A sample biographical sketch may be viewed at:
http://grants.nih.gov/grants/funding/modular/modular.htm.
- 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 citations.
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.
Submission Instructions
The title and number of this program announcement must be typed on line 2 of
the face page of the application form and the YES box must be marked.
Submit a signed, typewritten original of the application, including the
Checklist, and five signed photocopies in one package to:
CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
REVIEW CONSIDERATIONS
Applications will be assigned on the basis of established PHS referral
guidelines. Applications will be evaluated for scientific and technical merit
by an appropriate scientific review group convened in accordance with the
standard NIH peer review procedures. As part of the initial merit review, all
applications will 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 applications under review, will be discussed, assigned a
priority score, and receive a second level review by the appropriate national
advisory council or board.
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 likely 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 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 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 also will be reviewed with respect to the following:
o The adequacy of 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 also will be
evaluated.
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 they may be adversely affected by the project
proposed in the application.
AWARD CRITERIA
Applications will compete for available funds with all other recommended
applications assigned to the NICHD. 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.
INQUIRIES
Inquiries are encouraged. The opportunity to clarify any issues or questions
from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Steven Kaufman, M.D., M.S.
Center for Population Research
National Institute of Child Health and Human Development
6100 Executive Blvd., Room 8B13, MSC 7510
Bethesda, MD 20892-7510
Telephone: 301-496-4924
FAX: 301-480-1972
E-mail: sck@nih.gov
Diana Blithe, Ph.D.
Center for Population Research
National Institute of Child Health and Human Development
6100 Executive Blvd., Room 8B13, MSC 7510
Bethesda, MD 20892-7510
Telephone: 301-435-6990
FAX: 301-480-1972
E-mail: blithed@nih.gov
Direct inquiries regarding fiscal matters to:
Michael Loewe
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Blvd., Room 8A17, MSC 7510
Bethesda, MD 20892-7510
Telephone: 301- 435-7008
FAX: 301-402-0915
E-mail: ml70m@nih.gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance Nos.
93.866 and 93.864. Awards are made under authorization of Sections 301 and
405 of the Public Health Service Act, as amended (42 USC 241 and 284) and
administered under NIH grants policies and Federal Regulations 42 CFR 52 and
45 CFR Parts 74 and 92. This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or 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, and 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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