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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