SPINAL MUSCULAR ATROPHY, AMYOTROPHIC LATERAL SCLEROSIS, AND OTHER MOTOR NEURON DISORDERS Release Date: March 9, 2000 RFA: NS-01-004 National Institute of Neurological Disorders and Stroke THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THE RFA. Letter of Intent Receipt Date: June 1, 2000 Application Receipt Date: July 26, 2000 PURPOSE The purpose of this RFA is to solicit research on the etiology and treatment of spinal muscular atrophy, amyotrophic lateral sclerosis, and other motor neuron diseases. Considerable progress has been made in recent years toward understanding the biological bases of these diseases. In particular, important steps have been taken in identifying the genetic defects underlying certain motor neuron diseases, and in the development of animal models for these diseases. However, much remains to be learned about the mechanisms through which genetic mutations and other biological insults lead to pathology, and how these mechanisms may be manipulated therapeutically. This RFA will solicit novel approaches to understanding and treating motor neuron diseases, with emphasis on cellular, molecular, and high throughput approaches. RESEARCH OBJECTIVES Background Motor neuron diseases are among the most devastating of neurological disorders. These fatal diseases progressively paralyze the body, while leaving the mind intact and aware. The most common motor neuron diseases are spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Both of these diseases are comparatively frequent, with an annual incidence of 3 per 100,000 reported for ALS and a frequency of one in 10,000 live births observed for SMA. No cure, and little in the way of effective treatment, currently exists for these diseases. However, major advances have been made recently in our understanding of the genetic bases of these diseases, as well as in the molecular and developmental biology of motor neurons. Thus, now is an opportune time to launch a strong attack on these diseases. Both SMA and ALS have as their cardinal feature the loss of spinal motor neurons. In other respects, however, the two diseases are quite different. SMA generally has a very early onset (generally between 0 and 18 years), whereas ALS usually does not strike until middle age or later. SMA is an inherited disease and results from mutations in a single gene, the survival of motor neuron 1 (SMN1) gene. ALS has both familial and sporadic forms, and the familial forms have now been linked to several distinct genetic loci. ALS has prominent upper as well as lower motor neuron involvement, whereas SMA is confined to lower motor neurons. In addition to SMA and ALS, there are several other diseases that involve degeneration of lower and/or upper motor neurons. Of these, spinobulbar muscular atrophy (SBMA) is the most common. As the name implies, there are prominent bulbar signs and loss of brainstem motor neurons in this disorder. SBMA can have its onset in either childhood or adulthood. It is an X-linked recessive disorder resulting from an expansion of the CAG repeat in the androgen receptor gene. Despite differences in etiology, SMA, ALS, and other motor neuron disorders have commonalities in terms of potential treatment strategies. First, the fact that motor neurons are a relatively discrete, homogeneous, and well- characterized cell population makes these diseases particularly amenable to gene stem cell replacement therapy and/or gene therapy. Second, while the upstream events that trigger the onset of these diseases may differ, the fact that they specifically affect motor neurons raises the possibility of common downstream targets for drug intervention. The National Institute of Neurological Disorders and Stroke invites applications for research on the molecular and cellular mechanisms of SMA, ALS, and other motor neuron disorders, and on the development of potential therapeutics for these diseases. Studies using novel approaches or technologies or addressing novel hypotheses are particularly encouraged. Specific areas of interest include, but are not limited to, the topics listed below. Objectives and Scope Research Priorities for SMA Major strides were made recently in SMA research with the identification of the SMN gene and the development of the first animal models for SMA. Rapid progress has also been made in understanding the function of the SMN protein. Despite these important advances, however, our understanding of SMA remains fragmentary. In particular, very little is known about the natural history or cellular mechanisms of motor neuron loss in SMA. Central questions include the following: what is the time course of motor neuron loss relative to neuronal differentiation, axon outgrowth, target contact, and the development of presynaptic inputs? Do motor neurons differentiate in normal numbers and then die off, or is there also a failure of motor neuron differentiation? What proportion of motor neurons are lost by the time a patient or animal model shows signs of muscle weakness? Is ongoing motor neuron loss a significant component of the natural history of SMA? The answers to these questions are crucial for the rational design of therapeutics, and also to establish the developmental window during which such therapeutics are likely to be most efficacious. A second major area of inquiry concerns the molecular mechanisms through which mutations in the SMN gene lead to cellular pathology. There is now strong evidence that SMN normally functions to modulate RNA splicing, possibly via regulation of spliceosomal small nuclear ribonucleoprotein particle (snRNP) biogenesis. However, the precise mechanisms through which loss of SMN protein causes motor neuron death are unclear. In particular, there is a need to obtain more precise data about the spatial and temporal pattern of SMN1 expression in human and animal models, and to compare the normal time course of SMN expression with the time course of motor neuron development. Second, it will be important to determine when the first signs of motor neuron deterioration occur in SMN-deficient models relative to the normal time of onset of SMN1 expression. Finally, microarray-based profiling of gene expression in normal and SMN-deficient motor neurons should offer insights into the time course and molecular basis of motor neuron death. These and other research priorities for SMA are summarized below: O Determine the time course and cellular mechanisms of motor neuron loss in vivo, both in humans and in animal models O Develop additional animal models of SMA O Identify the RNA substrates on which SMN-regulated spliceosomes normally act (particularly those substrates specific to motor neurons) O Look for motor neuron-specific binding partners of SMN O Determine if SMN protein is involved in cellular functions other than RNA splicing O Understand the mechanisms regulating expression and function of the SMN1 and SMN2 genes O Elucidate the downstream molecular changes caused by loss of SMN function Research Priorities for ALS ALS has a more complex genetic basis than SMA, with only 5-10% of ALS cases being familial. Of these, 15-20% are due to mutations in the gene encoding Cu/Zn superoxide dismutase 1 (SOD). These appear to be gain-of-function mutations that confer toxic properties on the enzyme. The discovery of SOD mutations as a cause for ALS has allowed some progress to be made in understanding the disease: animal models for the disease are now available, and hypotheses are being developed and tested concerning the molecular events leading to cell death. Nevertheless, SOD mutations are responsible for a relatively small proportion of cases of familial ALS. A fuller understanding of ALS may therefore come from the study of other etiologies. Perhaps an even more pressing need, in terms of the number of patients affected, is to learn more about the causes of sporadic ALS. Recent work has demonstrated defective splicing of RNA for a glutamate transporter in a very high proportion (60-70%) of sporadic cases of ALS. Additional common molecular defects in sporadic ALS might be discovered through the use of genome scanning methods or high throughput analyses of gene and protein expression. Given the possible role of oxidative stress in the etiology of ALS, mitochondrial genes and proteins could be an important focus for such studies. These and other research priorities for ALS are summarized below: O Identify additional genetic loci associated with familial ALS O Look for acquired gene mutations in sporadic ALS O Perform global analyses of gene and protein expression in human and animal models of ALS O Identify new (non-SOD) animal models for ALS (for example, through collaborations with large-scale mouse mutagenesis centers) O Understand the mechanism of upper motor neuron cell death in ALS O Analyze cellular and molecular pathology of glial cells in human and animal models of ALS O Explore potential non-cell autonomous mechanisms of ALS O Proposals for research on normal and abnormal SOD function are not encouraged because this topic is already receiving relatively intensive study. Research Priorities Relevant to All Motor Neuron Diseases Although SMA, ALS, and SBMA have differences in etiology and clinical time course, all three diseases are characterized by the loss of spinal motor neurons. The reasons for the selective vulnerability of motor neurons in these diseases are not understood. This vulnerability does not appear to result from selective expression of mutant gene products: the SMN, SOD, and androgen receptor genes all are expressed in a variety of both neuronal and nonneuronal cell types in addition to motor neurons. However, it is possible that the development or maintenance of motor neurons requires unique proteins (or combinations thereof) that either by themselves or by the selective requirement for them render motor neurons especially vulnerable to changes in SMN, SOD, or androgen receptor gene function. Alternatively, the unusually high metabolic rates and/or long axonal projections of motor neurons may render them vulnerable via elevated requirements for common neuronal housekeeping proteins. In this regard, it is notable that different subsets of motor neurons are differentially affected in these disorders. Finally, it is of interest to note that defects in RNA splicing mechanisms have been implicated in both SMA and ALS. Thus, further study of RNA splicing mechanisms in motor neurons is clearly warranted. In particular, are there spliceosomal proteins or RNAs found only in motor neurons? Are there motor neuron-specific substrates for RNA splicing? Does the profile of motor neuron spliceosomal components or substrates change with age? SMA, ALS, and SBMA also have commonalities in terms of treatment strategy. Because these diseases involve loss of lower motor neurons, a relatively discrete and well-characterized cell population, they may be especially good targets for stem cell therapy. Purified motor neuron cell lines have been developed in vitro, and embryonic stem cells (ES cells) also show promise for replacing motor neurons. Further characterization and testing of these cells in vitro and in mouse models of motor neuron diseases are a high priority. An additional area of high priority is the development of high throughput methods for screening potential therapeutic agents. New methods in combinatorial chemistry have been used to generate large libraries of molecules, collections of natural products also exist. Screening of such collections may lead to the identification of therapeutic agents for motor neurons disorders. What is needed to unleash the potential of these libraries are high throughput assays with which to screen molecules for therapeutic activity. These assays could be either cell-free or whole-cell in vitro assays of the expression, activity, or aggregation of proteins implicated in motor neuron disease pathogenesis. Also of high priority is the development of efficient methods for secondary testing of therapeutic agents in animal models of motor neuron disease. These methods do not necessarily have to be limited to mouse models, but could include lower vertebrates and invertebrates (such as Drosophila) as well. O Understand why motor neurons are selectively vulnerable to the toxic effects of certain gene mutations O Characterize mechanisms and substrates of RNA splicing in motor neurons and define changes in these over the lifespan O Develop new motor neuron cell lines for transplantation or testing of therapeutic agents O Refine and test currently available stem cell lines for therapeutic efficacy in animal models, with emphasis on eventual application in humans O Develop high efficiency methods for gene delivery to motor neurons O Develop high throughput in vitro assays for screening potential therapeutic agents O Develop efficient assays for motor neuron function in animal models (for use in testing therapeutic agents or in identifying mutations affecting motor neurons in large-scale mutagenesis projects) O Identify early surrogate markers for motor neuron disease SPECIAL REQUIREMENTS During the course of the award period, the Principal Investigators may be invited to meet with NIH program staff in Bethesda, MD, to review scientific progress. Other scientists external to and knowledgeable about this area of research may also be invited to participate. Budget requests should assume that the travel funds will be needed for the PI to meet annually in the Washington, D.C. area, should such meetings be advisable. Progress toward understanding and treating motor neuron diseases will be facilitated by the timely and broad dissemination of research resources (including sequence data, animal models, cell lines, and technological advances) acquired by research funded by this RFA. Thus, applications submitted in response to this RFA must include a discussion of plans for making available data and materials acquired during the proposed project. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) and Exploratory/Development Research Grant (R21) award mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application for an R01 award submitted in response to this RFA may not exceed 5 years. The R21 awards are to demonstrate feasibility and to obtain preliminary data testing innovative ideas that represent a clear departure from ongoing research interests. These grants are intended to 1) provide initial support for new investigators, 2) allow exploration of possible innovative new directions for established investigators, and 3) stimulate investigators from other areas to lend their expertise to research within the scope of this solicitation. Applicants for the R21 must limit their requests to $100,000 direct costs per year and are limited to two years. These R21 grants will not be renewable, continuation of projects developed under this program will be through the regular research grant (R01) program. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is April 1, 2001. FUNDS AVAILABLE NINDS intends to commit approximately $3 million in FY 2001 to fund 8 to12 new grants in response to this RFA. An applicant may request a project period of up to 5 years for an R01 award and 2 years for an R21 award. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of NINDS 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 applications of outstanding scientific and technical merit. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Gabrielle G. Leblanc, Ph.D. Program Director, Neurodevelopment National Institute of Neurological Disorders and Stroke Neuroscience Center, Suite 2136, MSC 9523 6001 Executive Boulevard Bethesda, MD 20892-9523 (Rockville, MD 20852 for express, courier service) Phone: 301-496-5745 FAX: 301-402-1501 E-mail: GL54h@nih.gov Direct inquiries regarding fiscal matters to: Tina M. Carlisle Grants Management Specialist National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Suite 3264, MSC 9537 Bethesda, Maryland 20892-9537 Phone: (301) 496-3938 FAX: (301) 402-0219 Email: carlislt@ninds.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. 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 NINDS staff to estimate the potential review workload and plan the review. The Letter of Intent is to be sent to: Gabrielle G. Leblanc, Ph.D. Program Director Neurodevelopment Program National Institute of Neurological Disorders and Stroke Neuroscience Center, Suite 2136, MSC 9523 6001 Executive Boulevard Bethesda, MD 20892-9523 (Rockville, MD 20852 for courier service) Phone: 301-496-5745 FAX: 301-402-1501 E-mail: GL54h@nih.gov SCHEDULE SUMMARY Letter of Intent Receipt Date: June 1, 2000 Application Receipt Date: July 26, 2000 Peer Review Date: November 2000 Council Review: February 2001 Earliest Start Date: April 1, 2001 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. 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. In addition, the RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this in in pdf format. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS PHS 398 The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below. o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION: Use a Modular Grant Budget Narrative page (http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages). At the top of the page, enter the total direct costs requested for each year. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the current NIH salary cap level and the NIH policy for graduate student compensation in developing the budget request. o Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. o Provide an additional narrative budget justification for any variation in the number of modules requested beyond the first year. o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. -Complete the educational block at the top of the form page -List position(s) and any honors -Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years -List selected peer-reviewed publications, with full citations o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. 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 must be sent to: Dr. Lillian Pubols Scientific Review Branch National Institute of Neurological Disorders and Stroke 6001 Executive Blvd., Suite 3208, MSC 9529 Bethesda, MD 20892-9529 (Rockville, MD 20852 for express/courier service) Telephone: (301) 496-9223 FAX: (301) 402-0182 Email: LP28E@nih.gov 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by NINDS. If the application is not responsive to the RFA, NINDS 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 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 NINDS in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the NINDS National Advisory Council. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem or develop an important technology? If the aims of the application are achieved, how will scientific knowledge or technological capability be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o Adequacy of plans for dissemination of research resources: What is the likelihood that any research resources (including sequence data, animal models, cell lines, and technological advances) generated by the project will be made widely available in a timely fashion to the scientific community? Applicants should include in their applications a discussion of their plans for making available research resources acquired during the proposed project. The initial review group will be asked to comment the adequacy of these plans for making available research resources. Any opinions expressed by reviewers about this aspect of the proposal will be recorded as an administrative note. o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review), o adequacy of plans to make widely available to the research community all research resources developed during this project, o availability of funds, o programmatic priorities. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must 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. Revieweres are cautioned 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 Request for Applications (RFA), Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and Other Motor Neuron Disorders , 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 No. 93.853. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant 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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