Full Text AI-96-003
 
TRANSPLANTATION TOLERANCE
 
NIH GUIDE, Volume 25, Number 14, May 3, 1996
 
RFA:  AI-96-003
 
P.T. 34

Keywords: 
  Transplantation of Organs 
  Immunology 

 
National Institute of Allergy and Infectious Diseases
Juvenile Diabetes Foundation, International
 
Letter of Intent Receipt Date:  August 10, 1996
Application Receipt Date:  October 8, 1996
 
APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLICATIONS (RFA) MUST
BE PREPARED USING A MODIFIED (ABBREVIATED) GRANT APPLICATION FORMAT;
SPECIFIC INSTRUCTIONS FOR COMPLETING THE APPLICATION ARE IN AN NIAID
BROCHURE ENTITLED "INSTRUCTIONS FOR ABBREVIATED APPLICATIONS FOR
MULTI-PROJECT AWARDS" (February 1996).
 
PURPOSE
 
The National Institute of Allergy and Infectious Diseases (NIAID) of
the National Institutes of Health (NIH) and the Juvenile Diabetes
Foundation, International (JDFI) invite applications for basic, pre-
clinical and clinical studies to determine the mechanisms of
immunologic tolerance that will enhance solid organ and tissue graft
survival. This Request for Applications (RFA) for Program Project
Grants is intended to stimulate collaboration between clinicians and
basic immunologists to identify and characterize the immune
mechanisms responsible for enhancing graft survival by inducing
tolerance to the donor organ or tissue. The investigation of
tolerance induction for the prevention or treatment of autoimmune
disease could advance understanding of tolerance induction in the
transplant setting.  Thus, applications incorporating investigations
of tolerance induction for autoimmune disease in the transplant
setting are encouraged.
 
Applications should be submitted to and will be reviewed according to
usual NIH peer review procedures. Funds for each Program Project to
be awarded under this RFA will be provided by the NIAID and the JDFI.
To have an application reviewed and considered for funding,
applicants must authorize the NIAID, in writing, to provide to the
JDFI a copy of their letter of intent, application and NIH prepared
summary statement of the initial review
 
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 RFA,
Transplantation Tolerance, 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 Summary Report:  Stock No.  017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-0325 (telephone 202-512-1800).
 
ELIGIBILITY REQUIREMENTS
 
Research grant applications may be submitted by domestic for-profit
and non-profit organizations, public and private institutions, such
as universities, colleges, hospitals, laboratories, units of State
and local governments, and eligible agencies of the Federal
government.  Foreign organizations are not eligible to apply to the
NIH.  However, the JDFI will separately consider non-U.S.
applications (contact Sara King of the JDFI at 212-479-7524 for more
information).  Racial/ethnic minority individuals, women, and persons
with disabilities are encouraged to apply as Principal Investigators.
 
MECHANISM OF SUPPORT
 
The mechanism of support will be the program project (P01) grant.
This mechanism supports broadly based multi-disciplinary research
programs that have a well-defined central research focus, theme, or
objective.  An important feature of the program project is that the
interrelationships of the individual scientifically meritorious
projects will result in a greater contribution to the overall program
goals than if each project were pursued individually.  The program
project grant consists of a minimum of three interrelated individual
research projects that contribute to the program objective.  The
program project grant also can provide support for certain common
resources termed cores.  Such resources should be utilized by two or
more projects within the program project.
 
Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  The total
project period may not exceed five years.  At this time, the NIAID is
administratively limiting the duration of P01 grants to four years;
this administrative limitation may change in the future.  The
earliest anticipated award date is July 1997.
 
FUNDS AVAILABLE
 
The estimated total funds (direct and indirect costs) available for
the first year of support for this RFA will be $3.0 million:  $2.0
million from NIAID and $1.0 million from JDFI.  In fiscal year 1997,
the NIAID and the JDFI anticipate jointly funding approximately four
to five program projects related to this RFA.  Approximately 65
percent of the total costs of each grant will be funded by the NIAID
and approximately 35 percent by the JDFI. This level of support is
dependent on the receipt of a sufficient number of applications of
high scientific merit.  Applications may not request budgets in
excess of $750,000 Total Costs (direct and indirect) in the first
year.  NIH is currently limiting annual inflationary increases to no
more than four percent for future years.  Funding rules and policies,
including the determination of allowable indirect costs, of each
funding organization will be applicable.  Post award administration
will conform to current policies and requirements that govern the
research grant programs of the NIH and the JDFI as appropriate.
Although this program is provided for in the financial plans of the
NIAID and the JDFI, awards pursuant to this RFA are contingent upon
the availability of funds for this purpose.  Funding beyond the first
and subsequent years of the grant will be contingent upon
satisfactory progress during the preceding years and availability of
funds.  At this time, it has not determined whether or how this
solicitation will be continued beyond the present RFA.
Administrative adjustments in the project period and/or amount of
support may be required at the time of award.
 
RESEARCH OBJECTIVES
 
Background
 
In 1994, more than 19,000 solid organ transplants were performed in
the United States. Advances in surgical methods and current
immunosuppressive therapies have improved short-term survival;
however, long-term survival rates remain poor. For example, kidney
transplantation has a one-year graft survival rate of 85 to 95
percent; however, the survival rate at five years is about 50
percent. These short graft survival rates demonstrate the inadequacy
of the current clinical regimens to ensure long-term graft survival.
In addition, if organ failure is due to an autoimmune disease,
survival rates are significantly decreased. For example, diabetes,
which can cause end-stage diabetic nephropathy or systemic lupus
erythematosus, which can result in glomerulonephritis, can lead to
significantly decreased kidney graft survival rates at five years
post transplant.  The ability to induce donor-specific tolerance
could significantly improve long-term graft survival, reduce or
eliminate the continuing need for expensive, toxic and non-specific
immunosuppressive therapy and enhance the quality of life.
 
Recent investigations have provided insights into how transplant
tolerance may be accomplished.  Studies have demonstrated that
"passenger lymphocytes" carried within a transplanted organ may
affect graft survival.  This is particularly noticeable in liver
transplantation.  The liver, which contains a very large number of
lymphoid cells, does not induce an immune response leading to
rejection.  Instead, it appears to induce tolerance.  One possible
mechanism leading to this tolerance may be that the donor lymphoid
cells emigrate from the liver and take up residence in the
recipient's immune organs, such as the lymph nodes.  This
cohabitation of large numbers of donor lymphocytes with recipient
immune cells might "re-educate" the recipient immune system so that
the donor organ is not recognized as foreign.  In an attempt to mimic
this process, transfusions of donor blood or bone marrow have been
used to enhance solid organ graft survival in animal models and in
clinical trials.  These studies and trials have not yet provided
definitive results and the mechanisms whereby the introduction of
donor cells might lead to tolerance are still not understood.
Therefore, further pre-clinical studies are needed to help establish
the basis for clinical use of tolerance induction.
 
Basic research has shed light on some of the mechanisms involved in
tolerance induction.  An example is how co-stimulation can be
modulated to affect T-cell responses. Blockade of this "second
signal" during delivery of the antigen specific T-cell receptor
mediated "first signal" can result in antigen specific tolerance in
some animal transplant models.  In addition, experiments examining
the role of cytokines in modulating the immune response have shown
that the balance of cytokines can direct the immune response to
either the TH1 type of inflammatory response and graft rejection, or
to the TH2 type of suppressor/regulator response that might lead to
improved graft survival.  Although considerable progress has been
made in the past few years, it is clear that a better understanding
of how to manipulate the immune response to allow routine
donor-specific tolerance induction is required.
 
While these examples are illustrative of advances that have been made
already, the purpose of this RFA is to extend and expand research to
further the understanding of the processes and mechanisms leading to
transplant tolerance.
 
Research Objectives and Scope
 
The objectives of this RFA are to identify and characterize the
cellular and molecular mechanisms responsible for donor-specific
tolerance and to identify and examine approaches for modulating the
immune response to tolerize the transplant recipient. The scope of
research to be supported under this RFA includes, but are is not
limited to, the following broad areas of interest and examples of
possible specific investigations. The examples are not meant to be
directive, but illustrative of areas that remain to be investigated
further. Investigators are encouraged to develop novel approaches to
understanding the mechanisms responsible for the induction and
maintenance of donor-specific tolerance.
 
o  EVALUATIONS OF THE IMMUNE RESPONSE TO ORGAN ALLOGRAFTS AND
DEVELOPMENT OF WAYS TO MANIPULATE THE RESPONSE
 
Studies to determine the mechanism of action of HLA- derived peptides
and test the utility of these peptides in animal models and
transplant recipients.
 
The identification, assessment and investigation of the mechanisms of
therapies that modulate underlying autoimmune diseases, such as
insulin dependent diabetes mellitus (IDDM), to prevent damage to a
transplanted organ.
 
o  ELUCIDATION OF THE IMPORTANT CELLULAR AND MOLECULAR EVENTS OF BOTH
THE INDUCTION AND EFFECTOR PHASES OF THE IMMUNE RESPONSE
 
Investigations to determine the indicators of immune reactions that
are predictive of post-transplant graft survival and to develop
clinically useful post-transplant monitoring protocols capable of
predicting durable transplant tolerance.
 
Studies to determine the relative roles and mechanisms involved of
indirect vs. direct antigen presentation in the ability to induce
transplant tolerance and to design approaches to manipulate the
system to favor tolerance vs. destructive immune response.
 
Definition and characterization of the role of Major and Minor
Histocompatibility Antigens in both acute and chronic graft rejection
and development of regimens to ensure tolerance to these antigens to
promote long-term graft survival.
 
o  INVESTIGATIONS OF APPROACHES TO THE DEVELOPMENT OF THERAPEUTIC
STRATEGIES TO IMPROVE LONG-TERM GRAFT SURVIVAL.
 
Evaluations of the efficacy and mechanisms of action of multiple
agent interventional therapies in vivo in animal models of tolerance
induction in the presence or absence of current immunosuppressive
drug regimens.
 
Studies to delineate the mechanisms of action of immunomodulatory
molecules in transplant rejection and tolerance using appropriate
animal models, e.g., manipulating the immune system to affect the
balance of inflammatory vs. suppressive reactions by the use of
cytokines, receptors, competitors, inhibitors and mimicry molecules
delivered in vivo.
 
Development of approaches to promote transplant tolerance by treating
either the donor organs or recipients using gene therapy.
 
Proposed projects and the knowledge generated by this research must
be applicable to human disease and human transplantation.  Studies of
human transplantation in the setting of autoimmune diseases, such as
IDDM, are particularly sought.  While animal models may be proposed,
any such model must be an acceptable approximation of the human
condition. In addition, any proposed animal or human studies must
demonstrate the efficacy of the treatment under conditions of
generally accepted standard immunosuppressive therapy in humans.
Therefore, although studies focusing exclusively on infusion of donor
immune system cells will be considered, this type of study must be
focused on understanding the basic mechanisms of transplant tolerance
induction and maintenance.
 
SPECIAL REQUIREMENT
 
The NIAID and the JDFI plan to sponsor an annual meeting to encourage
the exchange of information among investigators supported under this
RFA, as well as to foster collaborative efforts and identify
resources that would enhance the productivity of this research
program.  Applications should include a statement indicating the
willingness of the applicant institution to participate in such
annual meetings.  For this purpose, travel funds for an annual
two-day meeting, to be held in the Washington, DC area, should be
included in the budget request.
 
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 sub-populations 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 new policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.
All investigators proposing research involving human subjects should
read 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 printed in
the NIH Guide for Grants and Contracts, Volume 23, Number 11, March
18, 1994.
 
Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES. Program staff may also provide
additional relevant information concerning the policy.
 
LETTER OF AUTHORIZATION
 
Applicants must submit a brief letter to the NIAID, co-signed by the
Principal Investigator and the official signing for the applicant
institution, indicating that they will allow their applications to be
considered for funding by the JDFI.  This letter may be combined with
the Letter of Intent or may be submitted directly to Dr. Stephen Rose
at the address shown in "INQUIRIES" below.  If a Letter of
Authorization is not submitted and signed by the appropriate
institutional officials, the application will be considered
incomplete and will be returned to the applicant without review.  All
materials relating to the application will be promptly forwarded to
the JDFI by the NIAID.  The summary statements for such applications
will be shared with the JDFI at the time of their availability.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by August 10, 1996, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address, and telephone number of the
Principal Investigator, a list of the key investigators and their
institution(s), and the number and title of this RFA.  Although the
letter of intent is not required, is not binding, does not commit the
sender to submit an application, and does not enter into the review
of subsequent applications, the information that it contains allows
NIAID staff to estimate the potential review workload and to avoid
conflict of interest in the review.
 
The letter of intent is to be sent to Dr. Stephen Rose, Ph.D. at the
address listed under INQUIRIES.
 
APPLICATION PROCEDURES
 
APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLICATIONS (RFA) MUST
BE PREPARED USING A MODIFIED (ABBREVIATED) GRANT APPLICATION FORMAT;
SPECIFIC INSTRUCTIONS FOR COMPLETING THE APPLICATION ARE IN AN NIAID
BROCHURE ENTITLED "INSTRUCTIONS FOR ABBREVIATED APPLICATIONS FOR
MULTI-PROJECT AWARDS" (February 1996).
 
Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 5/95).  Applications kits are
available at most institutional offices of sponsored research and may
be obtained from the Grants Information Office, Office 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.
 
For purposes of identification and processing, item 2 on the face
page of the application must be marked "YES" and the RFA number
"AI-96-003" and the words "Transplantation Tolerance" must be typed
in.
 
Applications must be received by October 8, 1996.  Applications that
are not received as a single package on the receipt date or that do
not conform to the instructions contained in PHS 398 (rev. 5/95)
Application Kit (as modified in, and superseded by, the NIAID
BROCHURE ENTITLED "INSTRUCTIONS FOR ABBREVIATED APPLICATIONS FOR
MULTI-PROJECT AWARDS"), will be judged non-responsive and will be
returned to the applicant.  The RFA label available in the
application form PHS 398 must be affixed to the bottom of the face
page.  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.
 
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 could be included
with the application.
 
It is highly recommended that the appropriate NIAID program contact
be consulted before submitting the letter of intent (See program
contact under INQUIRIES).
 
Submit a signed, typewritten original of the application, including
the checklist, and three signed, exact, single-sided 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 exact copies of the grant
application and all five sets of any appendix material must be sent
to Dr. Olivia Preble at the address listed under INQUIRIES.
 
Concurrent submission of an R01 and a Component Project of a
Multi-project Application: Current NIH policy permits a component
research project of a multi-project grant application to be
concurrently submitted as a traditional individual research project
(R01) application.  If, following review, both the multi-project
application and the R01 application are found to be in the fundable
range, the investigator must relinquish the R01 and will not have the
option to withdraw from the multi-project grant.  This is an NIH
policy intended to preserve the scientific integrity of a
multi-project grant, which may be seriously compromised if a strong
component project(s) is removed from the program.  Investigators
wishing to participate in a multi-project grant must be aware of this
policy before making a commitment to the Principal Investigator and
awarding institution.
 
SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO
THIS RFA
 
A status report on NIH reinvention activities was presented in the
NIH GUIDE (Vol. 24, No. 40, November 24, 1995.  Two of these
activities are: (1) the use of "Just-in-Time" grant applications; and
(2) modular budget requests and funding.  Both "Just-in-Time" and
"Modular Budgeting" together with special page limits on the research
plan are used for applications for this RFA.
 
JUST-IN-TIME GRANT APPLICATIONS.  The basic principle of
"Just-in-Time" is to simplify and reduce the administrative and
paperwork burdens of preparing an NIH grant application without
compromising the initial review group determination of scientific
merit or reasonableness of the proposed budget. To that end, both
less and less detailed information is required in "Just-in-Time"
applications.  Applications in response to this RFA are to use the
"Just-in-Time" format.
 
MODULAR GRANTS.  Applications are submitted and/or awards made with
direct costs in modules (multiples) of a given amount ($25,000 for
this RFA), with work proposed within these incremental categories.
The model involves using pre-established funding levels for awards
and acknowledging that grantees can and do rebudget post-award.  This
process eliminates the need for many budget details, thereby
relieving administrative burdens on both NIH staff and grantee
organizations and simplifying cost management by NIH program staff.
 
RESEARCH PLAN PAGE LIMIT.  Sections A - D of the research plan are
limited to 20 pages for: (1) the overview of the proposed program;
(2) each research project; and (3) each core.
 
The NIAID brochure, "INSTRUCTIONS FOR ABBREVIATED APPLICATIONS FOR
MULTI-PROJECT AWARDS", presents specific instructions for sections of
the PHS 398 (rev. 5/95) application form that should be completed
differently than usual.  Some sections in the application are
modified and others should not be completed for submission of the
application, but will be requested if the application receives a
score in the fundable range.  For all other items in the application,
follow the usual instructions on pages 5-20 of the PHS 398 booklet.
 
REVIEW CONSIDERATIONS
 
Review Procedures
 
Upon receipt, applications will be reviewed for completeness by the
NIH Division of Research Grants (DRG) and for responsiveness by NIAID
staff. 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 NIAID in accordance with the review
criteria stated below. As part of the initial merit review, a process
(triage) may be used by the initial review group in which
applications will be determined to be competitive or non-competitive
based on their scientific merit relative to other applications
received in response to the RFA. Applications judged to be
competitive will be discussed and be assigned a priority score.
Applications determined to be non-competitive will be withdrawn from
further consideration and the Principal Investigator and the official
signing for the applicant organization will be notified. The second
level of review will be provided by the National Advisory Allergy and
Infectious Diseases Council. In addition, the JDFI Lay Review
Committee and Board will review all applications.
 
Review Criteria
 
The general criteria for P01 grant applications are presented in the
NIAID BROCHURE.  Additional review criteria specific to this RFA are:
 
o  A well-defined, unifying goal or problem area of research to which
each project relates and contributes, thereby producing a research
environment that allows each research effort to share the creative
strengths of others.
 
o  A program director who possesses recognized scientific and
administrative competence.  He/she must demonstrate a substantial
commitment to the program in time and effort, thereby exercising
leadership in providing overall direction and in upholding rigorous
scientific conduct.
 
o  Each research project must, as assessed by peer review, stand on
its own independent scientific merit, as well as complement other
projects whenever feasible.
 
o  The projects require the participation of established
investigators in several disciplines or investigators with special
expertise in several areas of one discipline.  All investigators must
contribute to and share the responsibilities of fulfilling the
program objective.
 
o  In applications studying transplantation in an autoimmune setting,
the ability of the proposed research to provide knowledge of basic,
molecular and genetic mechanisms in the pathogenesis of the
underlying autoimmune disorder and the development of innovative
therapies for treating the human autoimmune disease to prevent
subsequent graft loss due to the autoimmune disease.  The
appropriateness of the proposed experimental plan to validate the
utility of the chosen strategy will be considered in this regard.
 
AWARD CRITERIA
 
Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, program priorities, and
the availability of funds.
 
INQUIRIES
 
Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.
 
Requests for the NIAID brochure "INSTRUCTIONS FOR ABBREVIATED
APPLICATIONS FOR MULTI-PROJECT AWARDS" as well as inquiries regarding
programmatic issues, may be directed to:
 
Stephen M. Rose, Ph.D.
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Disease
Solar Building, Room 4A14
6003 Executive Boulevard
Bethesda, MD  20892-7640
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-5598
FAX:  (301) 402-2571
Email:  sr8j@nih.gov
 
Direct inquiries regarding application preparation and review issues;
address the letter of intent, and mail two copies of the application
and all five sets of appendices to:
 
Oliva Preble, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C-19
6003 Executive Boulevard
Bethesda, MD  20892-7610
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-8208
FAX:  (301) 402-2638
Email:  op2t@NIH.GOV
 
Direct inquiries regarding fiscal matters to:
 
Ms. Victoria Putprush
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C-25
6003 Executive Boulevard
Bethesda, MD  20892-7610
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  vp8g@NIH.GOV
 
Schedule
 
Letter of Intent Receipt Date:  August 10, 1996
Application Receipt Date:       October 8, 1996
Scientific Review Date:         February 1997
Advisory Council Date:          May 1997
Earliest Award Date:            July 1997
 
AUTHORITY AND REGULATIONS
 
This program is supported under authorization of the Public Health
Service Act, Sec. 301 (c), Public Law 78-410, as amended. The
Catalogue of Federal Domestic Assistance Citation is No. 93.855 -
Immunology, Allergy, and Transplantation Research as appropriate.
Awards will be administered under PHS grants policies and Federal
Regulations 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.
 
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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