DEVELOPMENT OF HIGH RESOLUTION PROBES FOR CELLULAR IMAGING RELEASE DATE: September 9, 2003 RFA Number: RFA-RM-04-001 (formerly RFA-GM-03-013, see NOT-OD-04-008) Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATIONS: The National Institutes of Health (NIH) (http://www.nih.gov/) COMPONENTS OF PARTICIPATING ORGANIZATIONS: National Institute of General Medical Sciences (NIGMS) (http://www.nigms.nih.gov) National Institute of Biomedical Imaging and Bioengineering (NIBIB) (http://www.nibib.nih.gov) National Human Genome Research Institute (NHGRI) (http://www.genome.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: 93.859 (NIGMS); 93.286, 93.287 (NIBIB); 93.172 (NHGRI) LETTER OF INTENT RECEIPT DATE: October 20, 2003 APPLICATION RECEIPT DATE: November 20, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism 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 Institute of General Medical Sciences (NIGMS), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and the National Human Gnome Research Institute (NHGRI) invite applications for P20 Exploratory Center Grants to support multi-investigator teams to develop new technologies to enable higher sensitivity biological imaging in living cells. The purpose of this RFA is to encourage and facilitate novel, high-risk strategies to create fundamentally new probes with enhanced spectral characteristics with the goal of improving detection schemes by a factor of 10 to 100. Parallel improvements in probe targeting, cellular delivery, and signal detection will be required. The ultimate goal will be to develop probes that can be used to routinely achieve single molecule sensitivity for imaging dynamic processes in living cells. Although the focus of the RFA is on the development of probes for live cell imaging, the NIBIB will accept applications that emphasize pre-clinical development of imaging agents for the detection, diagnosis, or measurement of treatment efficacy for different disease processes. RESEARCH OBJECTIVES Background Recent growth in atomic level structural information, obtained through X- ray crystallography and nuclear magnetic resonance (NMR), has greatly increased our knowledge of biological structures. Despite the tremendous value of these structures, little is known about molecular movement, intracellular molecular dynamics, and the formation of transient assemblies inside the cell. Temporal or spatial relationships among individual molecules as they move within the cell cannot be captured by examining isolated static structures in vitro or by analyzing indirect biochemical or genetic data. Imaging organelle structure in frozen or fixed cells gives information about cellular context but is limited by its static 'snapshot' view. Dynamic imaging of molecules in vivo is required to track structural changes over time and to obtain direct information about native structures within the cell. Despite the increasing demand to image cellular processes, however, the tools and reagents are not well developed. The lack of sufficiently sensitive molecular probes and detection schemes for imaging individual molecules in vivo is a significant barrier to obtaining real-time information on dynamic cellular processes. A variety of probes are currently used for in vivo studies, but their chemical and photophysical properties limit their use and resolution within the 3-D context of the living cell. Detection in eukaryotic cells using currently available probes typically requires signals from tens to thousands of molecules. Problems with spectral intensity, photobleaching, isomerization, and large size limit their utility. Additional difficulties with probe targeting, cell delivery and detection instrumentation contribute to a detection sensitivity level that is estimated to be too low by a factor of 100-1000. The development of improved technology to increase the sensitivity of the probe signal 10-100 fold from what is currently possible would be a significant step forward. Scope of Research The objective of this RFA is to encourage and enable teams to initiate collaborative projects to develop new probes for molecular and cellular imaging. The overall goal is to establish programs to create complete toolsets for detection of single molecule events in living cells and to generate new strategies for dramatically increasing the resolution of imaging dynamic cellular processes. It is expected that new principles and high-risk approaches will be employed in the construction of probes. Although the probes developed under this RFA will be used for the study of basic molecular and cellular processes, the technology developed may eventually be adapted for clinical use. Examples of research that are appropriate for support by this RFA include: 1) Addressing the need for higher sensitivity and greater flexibility in probes for in vivo imaging 2) Addressing current bottlenecks related to spectral intensity, blinking, photobleaching, isomerization, signal-to-noise, and large size of labels 3) Developing new approaches to create genetically encoded probes with high quantum yield for routine detection of single molecules in vivo in eukaryotic cells; to develop probes that emit the maximum number of photons before bleaching 4) Identifying genetically encoded fluorescent proteins in nature that are superior to those currently used 5) Developing new strategies to create genetically encoded domains that 'capture' optically active, membrane permeable, diffusible probes 6) Exploiting in vitro evolution strategies to maximize the spectral characteristics of genetically encoded probes 7) Exploiting strategies in combinatorial chemistry or coordination chemistry to find new ways to intensify the probe signal 8) Creating multifunctional probes that generate a signal in more than one imaging modality (e.g., optical microscopy/electron microscopy, or x-ray/optical microscopy) 9) Developing new approaches to deliver and adapt inorganic materials (metallic colloids, magnetic nanoparticles, quantum dots, nanocrystals, or other) to the cellular environment; to address problems related to membrane permeability 10) Developing strategies for 'multiplexing' probe signals by combining or linking optically active molecules 11) Developing novel strategies for delivering probes into cells and for targeting specific molecules without disrupting cell physiology 12) Developing detection strategies and hardware to maximize signal amplification NHGRI, as a participant in this solicitation, is especially interested in technologies that fall under examples 3, 5, and 6 above, with emphasis on technologies that have a reasonable future potential to provide information regarding the dynamic presence, location, association, and/or activity of proteins. The participating Institutes strongly encourage potential applicants to discuss their ideas with Institute program staff and to send a letter of intent prior to submission to ensure that the application will be responsive to the mission and intent of this RFA. Exploratory Center Grant Activities Exploratory Center Grants will be expected to: 1) establish a collaboration that requires the interaction of a minimum of three to four investigators with different expertise spanning areas relevant to the development of the proposed technologies. These are likely to include investigators from the following areas: (i) molecular/cell biology, including delivery and targeting technologies; (ii) chemistry (especially synthetic organic chemistry and photochemistry); (iii) current cellular or molecular imaging methods; (iv) physical and engineering principles of the instrumentation used in cellular imaging; 2) establish a strategy for creating and testing new probes, including setting up the detection instrumentation and the model test system; and 3) develop methods for delivering probes into cells and targeting them to specific molecules. Groups of investigators at different institutions are welcome to apply. MECHANISM OF SUPPORT This RFA will use NIH P20 Exploratory Center Grant mechanism. Applicants will be solely responsible for planning, directing, and executing the proposed project. The earliest expected award date is July 2004. It is anticipated that this RFA will be re-issued for a second time with a submission deadline in late 2004 and an expected award date in 2005. P20 Exploratory Grants will not be renewable, but rather are expected to lead to more mature projects that can attract other sources of funding. Plans for subsequent full-scale imaging centers are under discussion and will depend upon the resources available for this activity. This RFA uses just-in-time concepts and the non-modular budgeting format (see http://grants.nih.gov/grants/funding/modular/modular.htm). Proposals to develop technologies to advance other aspects of imaging, but are not specifically designed to achieve single molecule detection in vivo or to amplify probe sensitivity, should be submitted in response to NIH's bioengineering announcements: http://grants.nih.gov/grants/guide/pa-files/PA-03-058.html http://grants.nih.gov/grants/guide/pa-files/PA-02-011.html FUNDS AVAILABLE The participating ICs intend to commit approximately $7 million in FY 2004 to fund seven to nine new P20 Exploratory Center 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 $500,000 per year. Costs for major items of equipment or indirect costs associated with consortium or sub-contractual arrangements will not be considered as part of the $500,000 direct cost limit. 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 Institutes include funds to support this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your domestic institution has any of the following characteristics: o 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 Applications from foreign institutions and for-profit organizations will not be accepted; however, participating collaborators can be at foreign institutions and for-profit organizations and may be included through subcontracts. 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 It is essential that the P20 Exploratory Center Grant be used to support a true collaborative team effort. Participating investigators may be at the same or different institution as the PI. A significant contribution from a chemist is a requirement; it will be the responsibility of the Principal Investigator (PI) to demonstrate how the chemist and the other collaborators will be integrated into the project. Ideally, since a minimum of three to four investigators will be included, each investigator must have primary expertise in different areas covering (i) molecular/cell biology, (ii) chemistry (especially photochemistry and synthetic organic chemistry), (iii) cellular imaging, and (iv) physics, engineering, instrumentation. The role and level of effort of each investigator should be justified within the context of the specific aims. A plan should be presented for coordination of the efforts of the individual investigators. This should include how (and how often) the team will meet and a description of the anticipated flow of work between the PIs that indicates how they will interact to accomplish the aims. The NIH is interested in ensuring that the information about new methods, technologies, and reagents developed through this program become readily available to the research community. Applicants should develop and propose specific plans for sharing of data, materials, and resources, taking into consideration the guidance issued by NIH http://ott.od.nih.gov/ and http://grants.nih.gov/grants/policy/data_sharing. The plans for sharing of data, materials and resources must be approved by NIH staff prior to award. 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: Catherine Lewis, Ph.D. Division of Cell Biology and Biophysics National Institute of General Medical Sciences Building 45, Room 2AS-13C Bethesda, MD 20892-6200 Telephone: (301) 594-0828 Email: lewisc@nigms.nih.gov Brenda Korte, Ph.D. Division of Discovery Science and Technology National Institute of Biomedical Imaging and Bioengineering 6707 Democracy Boulevard Suite 200 Bethesda, MD 20892-5469 Telephone: 301-451-4774 Fax: 301-480-4973 Email: kortebr@mail.nih.gov Adam L. Felsenfeld, Ph.D. Program Director Large-scale Sequencing National Human Genome Research Institute Building 31 Room B2B07 Bethesda, MD 20892-2033 Telephone: (301) 496-7531 Email: adam_felsenfeld@nih.gov o Direct your questions about instrumentation and software to: James F. Deatherage, Ph.D. Division of Cell Biology and Biophysics National Institute of General Medical Sciences Building 45, Room 2AS.13J Bethesda MD 20892-6200 Telephone: (301) 594-3828 Email: deatherj@nigms.nih.gov o Direct your questions about peer review issues to: Helen R. Sunshine, Ph.D. Office of Scientific Review National Institute of General Medical Sciences Building 45, Room 3AN.12F Bethesda, MD 20892-6200 Telephone: (301)594-2881 Email: sunshineh@nigms.nih.gov o Direct your questions about financial or grants management matters to: Grace Olascoaga Grants Management National Institute of General Medical Sciences Building 45, Room 2AN.32E Bethesda, MD 20892 Telephone: (301)594-5520 Email: olascoag@nigms.nih.gov Nancy Curling Acting Grants Management Officer National Institute of Biomedical Imaging and Bioengineering 6707 Democracy Blvd., Suite 900 Bethesda, MD 20892-2077 Telephone: 301-496-9315 Fax: 301-480-4974 Email: curlingn@mail.nih.gov Ms. Jean Cahill Grants Administration Branch National Human Genome Research Institute Building 31, Room B2B34, MSC 2031 Bethesda, MD 20892-2031 Telephone: (301) 402-0733 FAX: (301) 402-1951 E-mail: Jean_Cahill@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: Catherine Lewis, Ph.D. Division of Cell Biology and Biophysics National Institute of General Medical Sciences Building 45, Room 2AS-13C Bethesda, MD 20892-6200 Telephone: (301)594-0828 Email: lewisc@nigms.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://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. SUPPLEMENTARY INSTRUCTIONS This research solicitation is for high-risk exploratory studies to explore the potential of possible new enabling technologies. Proof of principle may be lacking in the preliminary data prior to submission, and obtaining it should be one of the goals of the research. Nevertheless, a complete research and development pathway leading to single molecular event detection should be proposed. The strategy should address all the steps needed to assemble the components of a complete system including delivery into cells, targeting, reporting, and detection. The timeframe for achieving the goals may be longer than five years; the proposal should present a plan for the first four years of support, but also address the longer term strategy. The total page limit for the sections "Background and Significance," "Progress Report and Preliminary Data," and "Research Design and Methods" is 15 pages. Specific Aims: It is anticipated that the initial coordination, strategy discussions, and planning will require time during the first year of the project, primarily because the nature of the research will be new and the groups may not be fully formed. Thus, it will be acceptable to include planning as a legitimate first step (aim) and to defer much of the experimental work for years 2-4 of the project, if necessary. For groups that are already working well together, however, it will be possible to initiate experiments soon after the award is made. Background and Significance: It is expected that the proposed research activities may not have been initiated. In these cases, the rationale for the research strategy should be developed from the published literature and not necessarily the applicants' own publications. Progress Report and Preliminary Data: Develop and describe the scientific rationale. It is expected that many of the most promising ideas relevant to this RFA will be untested and that most applicants will not have carried out systematic preliminary studies on the design of new probes. Unpublished preliminary data may exist on a new approach but may be in a relatively crude form. For these reasons, preliminary data (published or unpublished) are not required, should be kept to a minimum, and will not be a major criterion for review. More emphasis will be placed on development of the proposed strategy based on the combined insight, knowledge and experience of the collaborators. Applicants should discuss the qualifications of the collaborators and the criteria for selecting any additional collaborators who would participate but have not yet been recruited. Research Design and Methods: The general approach should be described. An explanation should be provided for how this approach will lead to increased sensitivity in signal detection. Relevant literature to support the potential of the proposed approach should be cited. The proofs of principle that must be obtained should be described. In view of the long-term nature and anticipated difficulty of the goals, elements of risk in approach and research plans are expected and acceptable. Nevertheless, the potential difficulties and feasibility issues must be addressed. Where specific solutions to them have not yet been identified, more general strategies should be proposed. A timeline for the project should be presented. This timeline should outline how the project's goals can be met within the time frame of the grant. Explicit, quantitative milestones should be presented, if possible. 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: http://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, three signed photocopies, and all five copies of appendix material, 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 must be sent to: Helen Sunshine, Ph.D. Office of Scientific review National Institute of General Medical Sciences Building 45 45 Center Drive, Room 3AN.12F, Bethesda, MD 20892-6200 APPLICATION PROCESSING: Applications must be received on or before 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the sponsoring ICs. 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 NIGMS in accordance with the review criteria stated below. As part of the initial merit review, all applications will: 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 written critique o Receive a second level review by an 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. The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment 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. 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? Because the goal of this solicitation is to encourage technology that has the potential to have significant impact on improving the state of the art, this criterion will be especially important. 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? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? This criterion will be especially important for this solicitation since the goal is to encourage novel technology with the potential to improve imaging resolution by several orders of magnitude. 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?) Since the purpose of this solicitation is to initiate new lines of inquiry, the applicant(s) need not have publications on the immediate research topic. However, applicants should have a record of accomplishment in relevant research areas and a history of innovative discovery and creativity. 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: Impact and the Acceptability of Risk: The purpose of this announcement is to recruit active established investigators to form multidisciplinary collaborations and develop new lines of inquiry. It is expected that most of the proposed research activities have not yet been initiated in the applicants' laboratories, and in some cases may be so new that they are not yet underway anywhere. Thus, the nature of the projects may be untested and risky, and the success may be difficult to predict. Evaluation of the application's merit should be made on the basis of the rationale and potential impact and the track records of the investigators. Technology Development: It is expected that the major focus of the P20 Exploratory Centers will be to develop technology with the goal of generating more sensitive imaging probes and imaging systems. Thus, the evaluation of merit will be based on the impact of the technology that is proposed. The biological aspects of the proposal will be secondary and will, for the most part, be used only to test the probes in the appropriate biological environments. The purpose will not be to discover new biological phenomena. PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below.) INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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 in the sections on Federal Citations, below.) CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS Sharing Research Data Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. Guidance issued by the NIH on the sharing of data, materials, and resources can be found at http://ott.od.nih.gov/ and http://grants.nih.gov/grants/policy/data_sharing. 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: October 20, 2003 Application Receipt Date: November 20, 2003 Peer Review Date: March/April 2004 Council Review: May 2004 Earliest Anticipated Start Date: July 1, 2004 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 SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking more than $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. See http://grants.nih.gov/grants/policy/data_sharing. Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. 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 http://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 http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284)and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm 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.


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