Selective Vulnerability of Fronto-Insular Network in Aging and Alzheimer's Disease

Selective Vulnerability of Fronto-Insular Network in Aging and Alzheimer's Disease is sponsored by National Institute on Aging. Investigates the selective vulnerability of the fronto-insular network in aging and Alzheimer's disease, focusing on cognitive decline mechanisms.

Expired PAR-17-047: Selective Cell and Network Vulnerability in Aging and Alzheimers Disease (R01) This notice has expired. Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) of Participating Organizations National Institute on Aging ( NIA ) Funding Opportunity Title Selective Cell and Network Vulnerability in Aging and Alzheimer’s Disease (R01) R01 Research Project Grant March 06, 2018 - This PAR has been reissued as PAR-18-706 .

Reminder: FORMS-E Grant Application Forms and Instructions Must be Used for Due Dates On or After January 25, 2018. - Updates to Active Funding Opportunity Announcements to Prepare for Policy Changes Impacting Due Dates On or After January 25, 2018. May 10, 2017 - New NIH "FORMS-E" Grant Application Forms and Instructions Coming for Due Dates On or After January 25, 2018.

See NOT-OD-17-062 . Funding Opportunity Announcement (FOA) Number Companion Funding Opportunity Additional Information on Eligibility . Catalog of Federal Domestic Assistance (CFDA) Number(s) Funding Opportunity Purpose The goal of this FOA is to define and characterize neural cell populations, neural circuits, and brain networks and regions that are vulnerable to brain aging and Alzheimer’s disease (AD).

Understanding mechanisms underlying selective vulnerability from cells to networks in AD is critical to fully define the disease process and to develop effective Open Date (Earliest Submission Date) Letter of Intent Due Date(s) 30 days before the application due date dates apply, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date. AIDS Application Due Date(s) New Date March 6, 2018 per issuance of PAR-18-706 .

(Original Expiration Date: October 6, 2019 ) It is critical that applicants follow the Research (R) Instructions (R&R) Application Guide , except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced.

Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV . When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information Part 2. Full Text of the Announcement I.

Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV.

Application and Submission Section V. Application Review Information Section VI. Award Administration Information Section VII.

Agency Contacts Section VIII. Other Information Full Text of Announcement Section I. Funding Opportunity Description Alzheimer’s disease (AD) is the leading cause of dementia in those over the age of 65, and as many as 5 million Americans age 65 and older have AD.

As the population ages, the number of people age 65 and older with AD is projected to increase between two and three-fold by 2050 without a cure or prevention of the disease. AD is one of the most persistent and devastating dementing disorders of old age because it eventually leads to a complete loss of memory and of the ability to function independently.

Currently there are only a few interventions that have been approved for the treatment of AD. Those approved have demonstrated only modest effects in modifying the clinical symptoms for relatively short periods, and none has shown a clear effect on disease progression. In response to this looming public health crisis in the United States, the National Alzheimer’s Project Act (NAPA) was signed into law in 2011.

The primary research goal of NAPA is to find effective interventions to treat and prevent AD and related dementias by 2025. As part of the strategic planning process for the implementation of the NAPA, two Alzheimer’s Disease Research Summits entitled Path to Treatment and Prevention were held in 2012 and 2015.

The overarching goal of the Summits was to bring together leading experts on Alzheimer’s disease to identify research priorities and strategies needed to accelerate the development of effective therapies across the disease AD is a heterogeneous, multifactorial disease that selectively affects certain regions of the brain (e.g. the entorhinal cortex, hippocampus and prefrontal cortex) while other areas, such as the cerebellum, remain unaffected.

Selective vulnerability in the nervous system refers to the fact that subpopulations of neurons in different brain areas may be more or less susceptible to specific types of environmental or pathological insults leading to cell dysfunction or death. The factors underlying this selectivity in AD remain unclear.

Recent studies on the staging of AD neuropathology showed AD-related tauopathy begins in the locus coeruleus, followed by neurofibrillary tangles in the entorhinal cortex, then hippocampal pyramidal neurons, and then neocortical neurons. Why is pathology seen in the locus coeruleus and entorhinal cortex at early stages of the disease? Why are specific neuronal cell types in these and other brain regions preferentially affected?

What is it about these cells and their projections that make them susceptible to amyloid and tau pathology? Recent studies using an epigenetic biomarker of tissue age (known as the epigenetic clock), which is based on DNA methylation levels, showed that the cerebellum ages more slowly than other parts of the human body in a population of supercentenarians.

How the cerebellum epigenetic clock compares with other brain area epigenetic biomarkers is unknown. Neuroimaging and anatomical studies have shown shrinkage or atrophy and synaptic changes in certain regions of the brain in aging and AD.

Functional imaging studies are defining changes in large-scale neural and cognitive networks in the aging human brain, and have shown, for example, specific disruption of the resting-state default mode network, compared to other networks, in AD.

Glia cells astrocytes, microglia, oligodendrocytes are critical for many normal brain functions; for example, astrocytes and microglia modulate the sculpting and turnover of synapses in development, adulthood and aging. Glial cell function changes with age and in AD: Are specific types of glial cells or their regional diversity susceptible to AD pathological processes?

Understanding the differential rate of brain regional and cellular aging will lead to novel insights into the molecular mechanisms of selective cell and network vulnerability to The selective vulnerability of specific cell types, and hence neural connectivity and network activity, is most likely due to the unique molecular properties of the affected cells.

Molecular characterization of neurons at the single-cell level using immunolabeling, RNA in situ hybridization, and transgenic labeling approaches has provided unique insight into individual gene expression in different cell types in different areas of the mouse brain. Current single-cell gene expression profiling approaches can measure genome-wide transcriptomics in single cells.

Integrated approaches have been described to sequence both genomic DNA and mRNA from the same cell, which would allow direct comparison of genomic variation and transcriptomic profiles in single cells. These single-cell genomic and molecular profiling approaches are critical to define and characterize mechanisms underlying selective cell vulnerability in aging and AD.

Such molecular signatures will suggest or confirm cellular pathways that may mediate vulnerability to (or resistance against) pathological processes in specific brain cells and regions in aging and AD.

For example, differential cell vulnerability might be expressed as differential adaptive responses to cell stressors (both internal and cell non-autonomous), calcium dyshomeostasis, mitochondrial/energy dysfunction, macromolecular damage, proteostasis disruption, and protein misfolding and aggregation.

Differential excitability and connectivity properties of neuronal subpopulations and their sensitivity to stress and environmental factors may contribute to and control selective network vulnerability in AD.

The goal of this FOA is to define and characterize neural cell populations (neurons and glia), neural activity and circuits, structural and functional networks, and brain regions that are vulnerable in brain aging and AD, and the mechanisms underlying such selective vulnerability.

Genetic and molecular signatures of different types of neurons and glial cells across the adult lifespan, in AD compared to other dementias of aging, and in different stages of AD will implicate cell processes and pathways mediating selective vulnerability to AD.

Defining cell types by physiological measures such as electrophysiology and connectivity and manipulating neural activity in circuits and networks will provide a functional index of selective vulnerability. Applications are encouraged to use new approaches to generate sophisticated data on molecular signatures of brain cells and on structure and function of brain circuits and networks.

Understanding the mechanisms underlying selective vulnerability from cells to networks in AD is critical to fully define the disease process and to develop effective therapies. Areas of research interest and opportunity include, but are Identification of neural cell populations, brain regions, neural circuits and/or large scale networks (connectomes) that contribute to vulnerability in brain aging and AD.

Comprehensive single-cell transcriptomics (e.g. RNAseq), epigenetics (e.g. chromatin remodeling, DNA methylation), and/or genomics (e.g. sequencing for somatic mutations) of neurons and glial cells in different brain regions at different ages and pathological stages of AD.

Multidisciplinary and multiplexed technological approaches to single-cell omics , electrophysiology and connectivity for comprehensive and integrative studies of selective vulnerability to neuro- and glial-degeneration Mechanisms underlying selective cell sensitivity to beta-amyloid, tau and other proteinopathies, including cell-to-cell spread of pathogenic proteins, and the role of proteostasis network function in selective cell and Role of cell-intrinsic versus cell non-autonomous and/or environmental factors in selective vulnerability or adaptive responses to cell or network stressors or neurodegenerative events.

Role of differential activity and connectivity properties of neuronal populations, circuits and networks in vulnerability (or resiliency) to Characterization of the molecular, cellular, synaptic and neural circuitry mechanisms underlying brain plasticity and resilience in counteracting vulnerability to neurodegeneration in aging and AD. VIII. Other Information for award authorities and regulations.

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity. Application Types Allowed Glossary and the SF424 (R&R) Application Guide provide details on Clinical Trials Not Allowed for due dates on or after January 25, 2018: Only accepting applications that do not propose clinical trials Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. NIA intends to commit $8M in FY2017 to fund 10-12 awards. Application budgets are not limited but need to reflect the actual needs of the proposed project.

The maximum project period is 5 years. NIH grants policies as described Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education: o Hispanic-serving Institutions o Historically Black Colleges and Universities (HBCUs) o Tribally Controlled Colleges and Universities (TCCUs) o Alaska Native and Native Hawaiian Serving Institutions o Asian American Native American Pacific Islander Serving Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Nonprofits without 501(c)(3) IRS Status (Other than Institutions For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Eligible Agencies of the Federal Government U.S. Territory or Possession Independent School Districts Public Housing Authorities/Indian Housing Authorities Native American Tribal Organizations (other than Federally recognized tribal governments) Faith-based or Community-based Organizations Non-domestic (non-U.S.) Entities (Foreign Institutions) Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to Foreign components, as defined in the NIH Grants Policy Statement , are allowed. Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted.

Registration can take 6 weeks or more, so applicants should begin the registration process as soon as Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number.

After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application. System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually .

The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code. Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.

must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants. gov registration.

eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to must have an active DUNS number and SAM registration in order to complete the Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account.

PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization 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 support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 This FOA does not require cost sharing as defined in the NIH Grants Policy Statement . 3.

Additional Information on Eligibility Applicant organizations may submit more than one application, provided that each application is scientifically distinct. The NIH will not accept duplicate or highly overlapping applications under review at the same time.

This means that the NIH will A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.

An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101 ). Section IV. Application and Submission Information Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA.

See your administrative office for instructions if you plan to use an institutional system-to-system solution. 2. Content and Form of Application Submission It is critical that applicants follow the Research (R) Instructions (R&R) Application Guide , including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise.

Conformance to the requirements in the Application Guide is required and strictly enforced.

Applications that are out of compliance with these instructions may be delayed or not accepted for For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant 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 By the date listed in Part 1.

Overview Information , prospective applicants are asked to submit a letter of intent that includes the following information: Descriptive title of proposed activity Name(s), address(es), and telephone number(s) of the PD(s)/PI(s) Names of other key personnel Participating institution(s) Number and title of this funding opportunity The letter of intent should be sent to: National Institute on Aging (NIA) All page limitations described in the SF424 Application Page Limits must be followed.

Instructions for Application Submission The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an All instructions in the SF424 (R&R) Application Guide SF424(R&R) Project/Performance Site Locations All instructions in the SF424 (R&R) Application Guide SF424(R&R) Other Project Information All instructions in the SF424 (R&R) Application Guide SF424(R&R) Senior/Key Person Profile All instructions in the SF424 (R&R) Application Guide All instructions in the SF424 (R&R) Application Guide must be followed.

Annual meetings of the awardees from this FOA will be convened by NIA and funds for travel of the PD/PI to the Bethesda, MD area to attend these meetings should be included in the budget.

All instructions in the SF424 (R&R) Application Guide PHS 398 Cover Page Supplement All instructions in the SF424 (R&R) Application Guide All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: Sharing Plan : Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification: All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. PHS Inclusion Enrollment Report Form only available in FORMS-D application packages for use with due dates on or before January 24, 2018.

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 PHS Human Subjects and Clinical Trials Information Form only available in FORMS-E application packages for use with due dates on or after January 25, 2018.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions: If you answered "Yes" to the question "Are Human Subjects Involved?"

on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record. Study Record: PHS Human Subjects and Clinical Trials Information All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study: All instructions in the SF424 (R&R) Application Guide must be followed. PHS Assignment Request Form All instructions in the SF424 (R&R) Application Guide Foreign (non-U.S.) institutions must follow policies Grants Policy Statement , and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide. 3.

Unique Entity Identifier and System for Award Management (SAM) See Part 1. Section III. 1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Part I.

Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next Organizations must submit applications to Grants.

gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons , NIH’s electronic system for grants administration. NIH and Grants.

gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants. gov on or before the application due date and time.

If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide. 5. Intergovernmental Review This initiative is not subject to intergovernmental All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .

Pre-award costs are allowable only as described in the NIH Grants Policy Statement . Requirements and Information Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission Electronically . If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must for Applicants Experiencing System Issues . For assistance with application submission, contact the Application Submission Contacts in Section VII .

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package . Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide. See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH.

Applications that are incomplete or non-compliant will not be Requests of $500,000 or more for direct costs in any year Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 Post Submission Materials Applicants are required to follow the instructions for post-submission materials, as described in the policy .

Section V. Application Review Information Only the review criteria described below will be considered in the review process.

As part of the NIH mission , all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each.

An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field. Does the project address an important problem or a critical barrier to progress in the field?

Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project?

If Early Stage Investigators those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)?

If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions?

Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project?

Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Additional Review Criteria As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials.

For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Inclusion of Women, Minorities, When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed.

For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals.

Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section .

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate Additional Review Considerations As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are