FUNCTIONAL HETEROGENEITY OF THE PERIPHERAL, PULMONARY AND LYMPHATIC
VESSELS
RELEASE DATE: September 24, 2002
RFA: HL-03-004
National Heart, Lung, and Blood Institute (NHLBI)
(http://www.nhlbi.nih.gov)
LETTER OF INTENT RECEIPT DATE: January 14, 2003
APPLICATION RECEIPT DATE: February 14, 2003
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations:
PURPOSE OF THIS RFA
The National Heart, Lung, and Blood Institute (NHLBI) invites
applications to address the functional heterogeneity of the arterial and
venous sides of the peripheral and pulmonary vessels as well as the
lymphatics. The purpose of this RFA is to support fundamental studies
focusing on the cellular and molecular mechanisms that contribute to the
functional differences which account for the heterogeneous nature of the
adult peripheral, pulmonary and lymphatic vessels. These studies are to
be limited to non-coronary arteries, pulmonary vessels, and the venous
and lymphatic circulations.
RESEARCH OBJECTIVES
Background
The economic and public health burdens of peripheral and pulmonary
vascular diseases and diseases of the lymphatics are immense,
contributing to increased morbidity and mortality especially as people
age. An important observation is that arteries, veins and lymphatics
are structurally and functionally heterogeneous, at the regional,
tissue, cellular and molecular levels. Examples are the blood-brain
barrier, the unique pulmonary circulation, blood flow regulation in the
various vascular beds, and localized vascular lesions. It is likely
that these structural and functional similarities and differences
contribute to the etiology of peripheral vascular, pulmonary and
lymphatic diseases. It is here that functional heterogeneity becomes
important physiologically, and especially in the treatment of the large
numbers of vascular diseases. Functional heterogeneity refers to the
phenotype (from the tissue, cellular and to the molecular levels) that
is unique to different vessels. These characteristics may be related to
the diverseness of the endothelial cells, myocytes and other components
of a particular vessel or even vascular bed, or may be regionally
specific within the same vessel or vascular bed. Understanding how all
the vascular components interact and contribute to the functional
heterogeneic nature of the vasculature is a neglected area in vascular
biology. New opportunities abound in unraveling this field with the
tools and approaches that are currently available to the investigator.
Therefore, a better understanding of the cellular and molecular factors
that contribute to this heterogeneity should provide insight into the
pathogenesis of peripheral vascular, pulmonary and lymphatic diseases,
and would lead to new and more effective treatments.
The derivation of vascular heterogeneity is multifaceted, beginning when
the nascent vasculature is laid down in the embryo. Structural and
functional changes occur during organogenesis, driven by genetic,
environmental, hormonal, hematologic and tissue specific factors, as
well as by intralumenal hemodynamic forces, eventually resulting in the
formation of the mature vessel. Although the mechanisms that drive
early vascular development are being actively pursued, very little is
known about the mechanisms contributing to structural and functional
remodeling of the nascent vessels that ultimately define the properties
of the adult vascular tree. Furthermore, most vascular studies focus
primarily on the arterial side of the circulation with few addressing
the venous and, fewer still, the lymphatic circulations.
The heterogeneity of the vasculature is further exemplified in the
interaction of blood proteins and cells with the vessel wall, where
these interactions may be modified by different shear forces and
inflammatory mediators of the disparate vascular beds. On the arterial
side, hemostatic balance is believed to be regulated by vascular bed-
specific endothelial cell signaling pathways, involving specific
endothelial gene expression unique to the vessel and regulated by
surrounding tissue. While some progress has been made with coronary
vessels, the peripheral arteries have been essentially neglected. On
the venous side, the etiology and risk factors for venous thrombosis are
different from those contributing to arterial thrombosis. Venous
thrombosis is most common in the lower extremities and is favored in
slow flow and low oxygen environments. The distinctive properties of the
venous endothelium, its response to shear forces, and its interaction
with blood proteins and cells leading to thrombus formation need to be
better understood.
Even within a specific vascular system, such as the pulmonary
circulation where there are phenotypic and functional differences in
vascular cells, the functional significance of these differences remains
to be resolved. Further still, the lymphatic circulation has a unique
position in its relationship to the arterial and venous circulations in
terms of vascular permeability, fluid transfer, macromolecular
homeostasis and immunity in that there is no heart to provide
hemodynamic pressure and propulsion, flow is obstructed easily, and
collaterals may not form. In congenital cases, lymphedema may be
asymmetric, even though a mutation is present throughout the body.
With respect to the vessel itself, the majority of studies continue to
focus on the inner and medial layers of the vessel rather than on the
outer wall. The outer wall, which includes the adventitial layer and in
certain vessels the vasa vasorum, has historically been assigned a
passive role of simply providing nutrients to the medial and inner
layers. Now, these layers are felt to play a significant role in
maintaining vessel integrity, and may contribute to the initiation and
progression of certain types of vascular disease. Little is known about
the phenotypic differences in these outer layers and how they contribute
to vascular functional heterogeneity.
The outcome of these studies ultimately should lead to better treatment
of peripheral vascular, pulmonary and lymphatic diseases, and may also
lead to the development of highly specific and dynamic imaging probes
that will provide for more accurate diagnoses and assessments of
treatment.
Objectives and Scope
This RFA will support studies on the cellular and molecular mechanisms
that contribute to the differences and functional heterogeneity of the
adult peripheral, pulmonary and lymphatic vessels. Although studies
that compare functional differences between dissimilar vascular systems,
such as pulmonary versus non-pulmonary vessels are encouraged, they are
not required. It is strongly encouraged that applicants propose studies
that will relate findings to the functional differences unique to a
particular vessel or vascular bed. Since there is little current
research explicitly designed to study vascular heterogeneity, these
studies may require interdisciplinary collaborations between vascular
cellular and molecular biologists, hematologists, clinicians and
vascular surgeons. Research aims that would be considered responsive
include, but are not limited to:
o studies on the factors involved with vessel maturation and remodeling
in different organs
o development and utilization of genetically engineered animal models
to study hemodynamic forces and vascular heterogeneity and function
o studies to differentiate the functional and genetic differences
between arterial, venous and lymphatic endothelial and smooth muscle
cells
o studies to address the metabolic and immunologic differences of the
arterial, venous and lymphatic circulations
o studies on the mechanisms controlling the homing behavior of
endothelial precursor cells and how this relates to vascular
heterogeneity
o mechanistic studies that focus on the role of the adventitia and vasa
vasorum in maintaining vessel integrity and in the initiation and
progression of disease
o studies on the factors which cause lymphatic and vascular
malformations
o studies that focus on the molecular characteristics of the leg veins
and their interaction with blood
o studies that investigate the properties of the peripheral and
pulmonary vascular signaling pathways and how perturbations lead to a
prothrombic state
o studies that address how specific differences in, for example,
endothelial cell surface receptors and adhesion molecules, permeability
and fluid transport properties, response to hypoxia or hyperoxia, or
interactions with other vascular cells influence development and
susceptibility to lung injury
o studies using hypoxia, including intermittent hypoxia, to elucidate
the basis of heterogeneity of different vascular beds
MECHANISM OF SUPPORT
This RFA will use the NIH R01 (investigator-initiated research project
grant) award mechanism. As an applicant you will be solely responsible
for planning, directing, and executing the proposed project. This RFA
is a one-time solicitation. Future unsolicited, competing-continuation
applications based on this project will compete with all investigator-
initiated applications and will be reviewed according to the customary
peer review procedures. The anticipated award date is September 30,
2003.
This RFA uses just-in-time concepts. It also uses the modular
budgeting format. (see
https://grants.nih.gov/grants/funding/modular/modular.htm).
Specifically, if you are submitting an application with direct costs in
each year of $250,000 or less, use the modular format.
FUNDS AVAILABLE
The NHLBI intends to commit approximately $4,000,000 in FY 2003 to fund
8 to 10 new and/or competitive continuation grants in response to this
RFA. An applicant may request a project period of up to four years and
a budget for direct costs of up to $250,000 per year. Because the
nature and scope of the proposed research will vary from application to
application, it is anticipated that the size and duration of each award
will also vary. Although the financial plans of the NHLBI to provide
support for this program, awards pursuant to this RFA are contingent
upon the availability of funds and the receipt of a sufficient number
of meritorious applications.
Since the total costs for a subcontract or consortium are included in
the direct cost request, one additional module of $25,000 above the cap
may be requested for the facilities and administrative costs associated
with third party agreements. A module requested for this purpose must
be clearly identified in the budget justification section of the
application, and will be restricted for this purpose only at the time
of award.
ELIGIBLE INSTITUTIONS
You may submit (an) application(s) if your institution has any of the
following characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges,
hospitals, and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign
o Faith-based or community based organizations
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to
carry out the proposed research is invited to work with their
institution to develop an application for support. Individuals from
underrepresented racial and ethnic groups as well as individuals with
disabilities are always encouraged to apply for NIH programs.
SPECIAL REQUIREMENTS
Grantees" Meetings
Upon initiation of the program, the NHLBI will sponsor annual meetings
to encourage the exchange of information among investigators who
participate in this program. In the preparation of the budget for the
grant application, applicants should factor in travel funds for the one
meeting each year to be held in Bethesda, Maryland. Applicants should
also include a statement in the applications indicating their
willingness to participate in such meetings. The first such meeting
likely will take place within 3 months of award.
Restrictions and Exclusions
Although studies that compare functional differences between dissimilar
vascular systems, such as pulmonary versus non-pulmonary vessels are
encouraged, they are not required. However, it is strongly encouraged
that applicants must propose studies that will relate findings to the
functional differences unique to a particular vessel or vascular bed. In
this regard, studies addressing the coronary arterial vessels will not
be considered responsive unless they focus on the adventitial layer or
the vasa vasorum.
Studies using human tissue will be considered responsive.
General Clinical Research Center
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.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA and welcome the opportunity
to answer questions from potential applicants. Inquiries may fall into
three areas: scientific/research, peer review, and financial or grants
management issues:
o Direct your questions about scientific/research issues to:
Dr. Stephen S. Goldman
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Rockledge 2
6701 Rockledge Drive, MSC 7956
Bethesda, MD 20892-7956
Telephone: (301)435-0560
FAX: (301) 480-2858
Email: goldmans@nhlbi.nih.gov
Dr. Dorothy B. Gail
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Rockledge 2
6701 Rockledge Drive, MSC 7952
Bethesda, MD 20892-7952
Telephone: (301)435-0222
FAX: (301) 480-3557
Email: gaild@nhlbi.nih.gov
Dr. Pankaj Ganguly
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Rockledge 2
6701 Rockledge Drive, MSC 7950
Bethesda, MD 20892-7950
Telephone: (301)435-0070
FAX: (301) 480-1046
Email: gangulyp@nhlbi.nih.gov
o Direct your questions about peer review issues to:
Dr. Anne P. Clark
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7214, MSC 7924
Bethesda, MD 20892-7924 (20817 for express/carrier service)
Telephone: (301)435-0270
FAX: (301) 480-0730
Email: clarka@nhlbi.nih.gov
o Direct your questions about financial or grants management matters
to:
Mr. Owen O. Bobbitt
Grants Operation Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Rockledge 2
6701 Rockledge Drive, MSC 7926
Bethesda, MD 20892-7926
Telephone: (301)435-0177
FAX: (301) 480-0422
Email: bobbitto@nhlbi.nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that
includes the following information:
o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA
Although a letter of intent is not required, is not binding, and does
not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review
workload and plan the review.
The letter of intent is to be sent by the date listed at the beginning
of this document. The letter of intent should be sent to Dr. Anne
Clark at the address listed under WHERE TO SEND INQUIRES.
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant
application instructions and forms (rev. 5/2001). The PHS 398 is
available at https://grants.nih.gov/grants/funding/phs398/phs398.html in
an interactive format. For further assistance contact GrantsInfo,
Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: All applications
submitted to this RFA must use the modular budget format. Applications
requesting up to $250,000 per year in direct costs must be submitted in
a modular grant format. Applications requesting one module ($25,000)
above the cap due to subcontract or consortium facilities and
administrative costs associated with third party agreements must also
be submitted in modular format and may request up to $275,000 per year
in direct costs. The modular grant format simplifies the preparation
of the budget in these applications by limiting the level of budgetary
detail. Applicants request direct costs in $25,000 modules. Section C
of the research grant application instructions for the PHS 398 (rev.
5/2001) at https://grants.nih.gov/grants/funding/phs398/phs398.html
includes step-by-step guidance for preparing modular grants.
Additional information on modular grants is available at
https://grants.nih.gov/grants/funding/modular/modular.htm.
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev.
5/2001) application form must be affixed to the bottom of the face page
of the application. Type the RFA number on the label. 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. The RFA
label is also available at:
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten
original of the application, including the Checklist, and three 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)
At the time of submission, two additional copies of the application and
five collated sets of appendix material must be sent to Dr. Anne Clark
at the address listed under WHERE TO SEND INQUIRES.
APPLICATION PROCESSING: Applications must be received by the
application receipt date listed in the heading of this RFA. If an
application is received after that date, it will be returned to the
applicant without review.
The Center for Scientific Review (CSR) 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 CSR 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.
Principal investigators should not sent supplementary material without
first contacting the Scientific Review Administrator (SRA). The SRA
will be identified in the letter sent to you indicating that your
application has been received. If you have not received such a letter
within three weeks after submitting the application, contact Dr. Anne
Clark at the address listed under WHERE TO SEND INQUIRES.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR
and responsiveness by the NHLBI. Incomplete applications will be
returned to the applicant without further consideration. And, if the
application is not responsive to the RFA, CSR staff may contact the
applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
applications at the next appropriate NIH review cycle.
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 NHLBI in accordance with the review
criteria stated below. As part of the initial merit review, all
applications will:
o Receive a written critique
o Undergo a process in which only those applications deemed to have the
highest scientific merit, generally the top half of the applications
under review, will be discussed and assigned a priority score
o Receive a second level review by the National Heart, Lung and Blood
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 your application in order to judge the likelihood
that the proposed research will have a substantial impact on the
pursuit of these goals:
o Significance
o Approach
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these
criteria in assigning your application"s overall score, weighting them
as appropriate for each application. Your 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,
you 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 your study address an important problem? If the
aims of your application are achieved, how do they advance scientific
knowledge? 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? Do you acknowledge potential problem areas and
consider alternative tactics?
(3) INNOVATION: Does your project employ novel concepts, approaches or
methods? Are the aims original and innovative? Does your project
challenge existing paradigms or develop new methodologies or
technologies?
(4) INVESTIGATOR: Are you appropriately trained and well suited to
carry out this work? Is the work proposed appropriate to your
experience level as the principal investigator and to that of other
researchers (if any)?
(5) ENVIRONMENT: Does the scientific environment in which your 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?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your
application will also be reviewed with respect to the following:
o PROTECTIONS: 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.
o INCLUSION: The adequacy of plans to include subjects from both
genders, all racial and ethnic groups (and subgroups), and children as
appropriate for the scientific goals of the research. Plans for the
recruitment and retention of subjects will also be evaluated. (See
Inclusion Criteria included in the section on Federal Citations, below)
o BUDGET: The reasonableness of the proposed budget and the requested
period of support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: January 14, 2003
Application Receipt Date: February 14, 2003
Peer Review Date: June/July, 2003
Council Review: September 4-5, 2003
Earliest Anticipated Start Date: September 30, 2003
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
REQUIRED FEDERAL CITATIONS
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research
projects unless a clear and compelling justification is provided
indicating 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 clinical research should read the AMENDMENT
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research - Amended, October, 2001," published in the NIH Guide
for Grants and Contracts on October 9, 2001
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html),
a complete copy of the updated Guidelines are available at
https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_
2001.htm. The amended policy incorporates: the use of an NIH definition
of clinical research, updated racial and ethnic categories in
compliance with the new OMB standards, clarification of language
governing NIH-defined Phase III clinical trials consistent with the new
PHS Form 398, and updated roles and responsibilities of NIH staff and
the extramural community. The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or
proposals and/or protocols must provide a description of plans to
conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable, and b)
investigators must report annual accrual and progress in conducting
analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN
SUBJECTS: The NIH maintains a policy 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
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 that is available at
https://grants.nih.gov/grants/funding/children/children.htm.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH
policy requires education on the protection of human subject
participants for all investigators submitting NIH proposals for research
involving human subjects. You will find this policy announcement in the
NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT:
The Office of Management and Budget (OMB) Circular A-110 has been
revised to provide public access to research data through the Freedom of
Information Act (FOIA) under some circumstances. Data that are (1)
first produced in a project that is supported in whole or in part with
Federal funds and (2) cited publicly and officially by a Federal agency
in support of an action that has the force and effect of law (i.e., a
regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has
provided guidance at
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this PA in a public
archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application
should include a description of the archiving plan in the study design
and include information about this in the budget justification section
of the application. In addition, applicants should think about how to
structure informed consent statements and other human subjects
procedures given the potential for wider use of data collected under
this award.
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. Furthermore, we caution reviewers that their anonymity
may be compromised when they directly access an Internet site.
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 RFA is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at
www.health.gov/healthypeople.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of
Federal Domestic Assistance No. 93.837, 93.838, and 93.839 and is not
subject to the intergovernmental review requirements of Executive Order
12372 or Health Systems Agency review. 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 described at https://grants.nih.gov/grants/policy/policy.htm
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92
The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the 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.