It is critical that applicants follow the Research (R) Instructions in the SF424 (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

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Background

Molecular analysis of brain tissue typically relies on ensemble averaging of heterogenous mixtures of cell types within a specific brain region. However recent technological advances enable molecular characterization of large numbers of individual cells. Single cell approaches can uncover effects on rarer cell types and have the potential to reveal cellular differences resulting from specific niche environments or transitory cellular states. Some single cell technologies in use include single cell RNA-sequencing (scRNA-seq), single nucleus RNA-sequencing (snRNA-seq), single cell ATAC-seq, single cell Hi-C, and spatial genomics approaches such as multiplexed FISH. Individual researchers as well as large project teams including the Human Cell Atlas, Common Fund HuBMAP, and NIH BRAIN Initiative Cell Census Network (BICCN) are exploiting these technologies to 1. understand how individual cells within a tissue or region differ, 2. identify the spectrum of human cell types, 3. reveal how distinct cell types interact with one another, and 4. elucidate functions of human cell types in health and disease.

Chronic exposure to opioids can lead to long term changes in brain function and to opioid use disorder (OUD). Many brain regions are involved in addictive processes including the prefrontal cortex, nucleus accumbens, ventral tegmental area, striatum, insula, amygdala, and hippocampus. Despite great advances in our understanding of molecular pathways and circuits involved in substance use disorders such as OUD, there remains limited knowledge concerning 1. the specific types and numbers of cells within these brain regions, 2. how these cells differ from one another with respect to gene expression, and 3. the changes associated with chronic opioid exposure that occur at the single cell level.

Antiretroviral therapy has, in large part, transformed the HIV epidemic into a chronic manageable disease in the United States. However, people living with HIV remain at higher risk for impaired cognitive functions (e.g. HIV-Associated Neurocognitive Disorder or HAND) and exhibit higher rates of legal and illegal drug use. Opioid use by HIV-infected individuals has the potential to further diminish immune function and/or exacerbate HIV-related CNS impairment. However, little is known about 1. the molecular characteristics of CNS cell types that might preferentially harbor HIV, 2. the effects of persistent HIV infection or HIV treatment regimens on specific CNS cell types within key brain regions, or 3. how chronic opioid use might modify these effects. Single cell technologies have the potential to shed light on these processes.

RFA-DA-19-037 Single Cell Opioid Responses in the Context of HIV (SCORCH) Program: CNS Data Generation (UM1) will support projects proposing to generate single cell or single nucleus RNA-sequencing data sets for at least one brain region relevant to persistent HIV infection and opioid use disorder. If fully successful, this project will generate 1. a cellular parts list for at least one NIDA-relevant brain region, 2. reveal how cell types within this brain region differ from one another with respect to gene expression, potentially enabling cell type-specific genetic or pharmacological manipulation, 3. reveal how HIV infection in the CNS influences single cells and the genes expressed within them, providing potential targets for manipulation of HIV persistence and/or HIV neurobiological sequelae, 4. reveal how cell types within this brain region are altered by chronic opioid exposure providing potential novel therapeutic targets for opioid addiction, and 5. uncover potential synergistic effects of chronic opioid exposure and HIV infection in the CNS.

In parallel through RFA-DA-19-038, a SCORCH data coordination, analysis, and scientific outreach center will be established to standardize and share single cell molecular HIV/SUD data generated by this program by ensuring that the data is FAIR (Findable, Accessible, Interoperable, and Reusable). The SCORCH Data Center will also integrate other molecular HIV/SUD data sets generated by NIDA-funded investigators to maximize their value to the scientific community. This data center is expected to leverage knowledge and resources generated by BICCN, HuBMAP, and other single cell initiatives to maximize scientific understanding. Harmonized molecular and single cell HIV/SUD data sets will enable near term data mining by the scientific community to identify HIV and/or SUD biomarkers and identify candidate pathways for therapeutic intervention. The SCORCH Data Center will also enable future mining of these data sets as new and improved data science and information technology approaches are developed, maximizing NIDA’s original investment in the data generating activities.

Goals

The purpose of this FOA is to support generation of single cell RNA-sequencing datasets for at least one brain region relevant to persistent HIV infection and opioid use disorder. Applications that are not responsive to this FOA will be returned without review. To be responsive to this FOA, proposed projects should be framed to answer one or more vexing questions about persistent HIV infection in the CNS. The major thrust of the proposed project also MUST:

• exploit single nucleus or single cell transcriptomic assays with the goal of identifying the types of cells within at least one NIDA-relevant brain region (e.g. PFC, NAc, VTA, striatum, insula, or other appropriately justified region) and how the cell types and individual cells within that region differ from one another in terms of gene expression.
• focus on human post-mortem brain tissue from controls, individuals with chronic opioid exposure, HIV-infected individuals, and HIV-infected individuals with chronic opioid exposure.
• propose to detect HIV proteins or RNA or DNA within the single cells or nuclei to be assayed.

Applicants are encouraged to contact program staff to answer any questions they may have and are welcome to consider the following when designing their proposed projects:

• Interdisciplinary teams will be necessary for successful completion of the proposed work. Such teams should include expertise in the generation of single cell or single nucleus transcriptomes, analysis of single cell data, HIV persistence or effects on the CNS, and the effects of chronic opioids or other drugs on the CNS.
• Our knowledge concerning the extent to which persistent HIV resides in particular brain regions and cells is limited, therefore preliminary data supporting a connection between HIV-related CNS phenotypes and a particular brain region or cell type is not required. Applicants may propose pilot experiments to survey bulk tissue to help address this issue and aid in interpretation of single cell data generated.
• Applicants may propose a single cell discovery or survey phase followed by a data production phase or may propose a combination of shallow and deep assay strategies to maximize understanding of the brain region of interest.
• Applicants may propose to use capture methods or other purification techniques to isolate one or more specific high value cell types (e.g. microglia) to gain a deeper understanding of the gene expression variation within that cell type.
• Post-mortem brains or tissue can be obtained from a variety of sources including NeuroBioBank and the National NeuroAIDS Tissue Consortium (NNTC).
• Additional single cell assays (e.g. ATAC-seq, DNA methylation, spatial genomics) and other assays may be proposed with appropriate justification.
• Ancillary single cell studies on the homologous brain region in other model systems may be proposed, with justification, to help differentiate between HIV-related or opioid-related effects. No more than 10% of the proposed budget should be devoted to this activity.
• Applicants may propose to analyze their findings by integrating the single cell data generated with existing single cell and other molecular data sets including those from cell culture, rodents, primates, this program, and other programs that involve opioid exposure and/or HIV infection.
• Applicants should propose to functionally test high priority findings using cell culture, animal models, organoids or other strategies.

See Section VIII. Other Information for award authorities and regulations.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from 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 Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• 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
• Regional 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 apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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 possible. The NIH 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 late submission.

• Dun and Bradstreet 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) 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.
• o   NATO 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.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. 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 submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program 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.

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 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

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 not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• 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).

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace 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.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, 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 review.

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.

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: NIDALetterofIntent@mail.nih.gov

Applicants are encouraged to send the letter of intent by email to the email address above but as an alternative the letter may also be sent to:

Office of Extramural Policy and Review
National Institute on Drug Abuse/NIH/DHHS
6001 Executive Boulevard, Suite 4243, MSC 9550
Bethesda, MD 20892-955

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed with the following exceptions:

Specific Aims: 1 page limit

Tissue Component: 6 page limit

Assay Component: 6 page limit

Data Deposition and Analysis Component: 6 page limit

Prioritization and Functional Verification Component: 6 page limit

Research Management Component: 6 page limit

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: The overall SCORCH program goal is to support generation of single cell or single nucleus RNA-sequencing datasets for at least one brain region relevant to persistent HIV infection and opioid use disorder. Describe the specific aims of the UM1 for the performance period of this project.

Research Strategy:

Tissue Component: Describe source(s) of tissue, how the brains or tissue were collected and stored, post-mortem index assessment, and justification for the selection of the brain region(s) to be characterized. Discuss how the quality of tissue will be assessed including how artifactual ischemic effects can be avoided and how brain regions will be identified and dissected. Describe the anticipated numbers of brains of each type (control, HIV+, HIV+ OUD+, and OUD+) to be assayed, and the phenotypic assessments included with respect to relevant HIV or OUD associated phenotypes. These phenotypes might include viral load, antiretroviral therapy regimen, ART treatment interruptions, cognitive or neurological assays, type and amounts of opioid(s) used through self-report and/or toxicology, other indications of severity of OUD, OUD treatment regimens, etc. Describe how comparisons between groups will be matched in terms of age, sex, and other relevant characteristics.

Assay Component: Describe proposed single cell or single nucleus assays including information about tissue handling, library preparation, numbers and types of cells and transcripts expected to be assayed, previous success at generating large amounts of single cell or single nucleus data from eukaryotic tissues, and potential pitfalls and alternative approaches. Include a power analysis indicating the estimated number of samples to be assayed from each of the four groups as well as the number of single cells to be assayed from each sample. If the proposed budget is insufficient to achieve the necessary power, applicants may propose a pilot study within the budget limitations and describe how the pilot study will significantly move the field forward.

Data Deposition and Analysis Component: Describe how the team will develop and use common metadata and data standards, adopt data quality metrics, analyze single cell data (including integration of this data with other relevant molecular or single cell data sets), and share protocols and data with the scientific community, as appropriate and consistent with achieving the goals of the program. Describe any innovative analysis strategies that will be used.

Prioritization and Functional Validation Component: Describe plans for prioritization and functional validation of high priority discoveries made using the single cell data generated. In silico, cell culture, organoid, animal model, high throughput knockdown or activation, or other approaches may be proposed. No more than 10% of the proposed budget should be allocated for this activity.

Research Management Component: Describe research management plans including plans for interacting with the SCORCH Data Center and other data generators that may be part of the SCORCH consortium. Provide a timeline and detailed quantitative annual milestones for the entire funding period. As a part of the quantitative milestones, applicants must describe the total number of single cell or single nucleus transcriptomes and other assays that will be completed for each year of the project period and by the end of the project period. Applicants should also indicate the total number of samples from each group (control, HIV+, HIV+ OUD+, and OUD+) that will be assayed by the end of the project period. If selected for funding, applicants will work with NIH staff to develop more granular quarterly milestones. Applicants should plan for the PDs/PIs and essential team members to travel domestically for a yearly face to face meeting for the entire funding period.

Resource 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 modifications:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

A primary goal of this program is to facilitate discoveries by the broad scientific community. Restrictive sharing practices and licensing terms for program-generated data and resources could substantially diminish their value and public benefit. Accordingly, awardees are expected to manage data, resources, protocols, and software in a way that achieves this goal.

Applicants should indicate their willingness to abide by all data deposition, quality control metrics, standardization, metadata requirements, data and software release, and public copyright license policies developed by the SCORCH Steering Committee and approved by NIH staff. The development of policies, methods, and standards for such sharing is critically important.  The NIH expects that the awardees, through the SCORCH Steering Committee, will develop such policies, methods, and standards in concert with the NIH. These policies, methods, and standards must remain consistent with NIH-wide policies on data and resource sharing.

Data will be made available through the SCORCH program portal as appropriate via the SCORCH Data Center. The SCORCH portal will serve as the central access point for information regarding data, critical tools, protocols, and reagents developed by this program.

SCORCH program data will also be deposited by the SCORCH Data Center into appropriate public or controlled-access data repositories. Applicants should identify such repositories and describe plans for deposition. For datatypes that lack suitable public repositories, applicants should indicate their willingness to identify an appropriate alternative solution consistent with achieving the goals of the program.

Genomic Data Sharing Plan:  If applicants propose to generate genomic data, they must indicate their willingness to abide by the NIH Genomic Data Sharing Policy (https://gds.nih.gov/) and should indicate their agreement to it in the data sharing plan. 

Sharing within the SCORCH Program: The SCORCH program aims to maximize the benefits of sharing, while protecting the intellectual property of the data generators. Prepublication sharing of data within the SCORCH consortium will allow collaboration across initiatives and further program progress towards its goals and objectives. Therefore, this program expects that data, metadata, and resources generated be made available to other SCORCH program members immediately upon being considered "shareable", as appropriate and consistent with achieving the goals of the program. When program-generated material under embargo is shared within the program, it will be considered confidential with the understanding that the information will not be used or disclosed by program members unless explicitly agreed upon by the originator of the data under mutually acceptable terms. That is, consortium members may not publish using material generated by other consortium members without a collaboration or other agreement, or until the material in question has been made available to the public or until 12 months has passed, whichever is earliest.

Applicants are expected to register resources supported by this FOA in the Neuroscience Information Framework  https://scicrunch.org/ and use Research Resource Identifiers (RRID) assigned by http://scicrunch.com/resources in any publication supported by this FOA.

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) 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 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

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions.

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 Grants.gov

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 business day.

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 Submission.

Applicants 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.

This initiative is not subject to intergovernmental review.

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.

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 process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

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 and responsiveness by NIDA, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Only the review criteria described below will be considered in the review process.

Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

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 project proposed).

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 the prior research that serves as the key support for the proposed project rigorous? 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 drive this field? Will the proposed study transform our ability to understand the brain effects of HIV infection, or chronic opioid exposure or both? Will the study inform the design of novel genetic or pharmacological tools to manipulate the brain region(s) or cell types being investigated? Will the proposed work advance our ability to understand and develop new therapeutic approaches to treat opioid use disorder and/or the neurological sequelae of persistent HIV infection?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or 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 team have appropriate expertise in opioid use disorders? Does the team have appropriate expertise in HIV infection and pathology especially with respect to the CNS? Does the team have appropriate expertise and a good track record in generating production level or large quantities of high quality single cell or single nucleus data? Does the team have expertise in analyzing single cell/nucleus data sets?

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? Does the applicant propose novel single cell/nucleus data generation techniques, strategies, and/or analysis approaches?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed 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? 

Is the overall strategy appropriate for accomplishing the proposed aims of the project? Does the team have access to the tissues required for the proposed experiments? Will the proposed approach enable the generation of large numbers of high quality single cell or single nucleus data sets? Is the proposed single cell/nucleus data analysis plan appropriate? Are the planned prioritization and functional validation of high priority discoveries appropriate? Is the projected timeline feasible and appropriate? Are the proposed milestones quantitative and appropriate for each phase of the project?

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 individuals of all ages (including children and older adults), 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? Does the team have access to appropriate equipment required for single cell or single nucleus data generation and analysis?

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.

For research that involves human subjects but does not involve one of the 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 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 Subjects.

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 individuals of all ages (including children and older adults) 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 in Clinical Research.

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 protection is proposed.

Not applicable

Not applicable

Not applicable

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.

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 reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by CSR, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council on Drug Abuse. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for the SCORCH program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below. Awardee will retain custody of and have primary rights to the data and software developed under this award, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

The PD(s)/PI(s) will have the primary responsibility for:

• Determining research approaches, designing protocols, setting project milestones, and conducting research.
• Participating in group activities, including a Consortium-wide SCORCH Program Steering Committee and subcommittees as needed.
• The SCORCH Consortium will meet in person yearly and the SCORCH Program Steering Committee will recommend the frequency of other in-person and teleconference meetings as needed. 
• Providing reports and data in a timely fashion as agreed upon by the SCORCH Program Steering Committee.
• Submitting all data as soon as they are collected to the SCORCH Data Center for quality control.
• Preparing abstracts, presentations and publications and collaborating Consortium-wide in making the public and professionals aware of the program.
• Assessing and disseminating data, protocols, and methods developed for or derived from the SCORCH program within and outside the Consortium.
• Adhering to policies regarding data sharing and publication established by the NIH and the SCORCH Program Steering Committee.
• Abiding by common definitions, protocols, and procedures, as chosen by majority vote of the SCORCH Program Steering Committee.
• Submitting periodic progress reports in a standard format, as agreed upon by the SCORCH Program Steering Committee and NIH SCORCH Working Group.
• Attending and participating in SCORCH Program Steering Committee meetings and accepting and implementing decisions by the NIH SCORCH Working Group, as appropriate.

NIH staff will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• The NIH SCORCH Working Group will consist of program staff from NIDA and possibly other NIH institutes.

The NIH Project Scientist(s) will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination.  However, the role of NIH staff will be to facilitate and not to direct the activities.  The Project Scientist(s) will participate as members of the SCORCH Program Steering Committee and, the Project Scientists together will have a single vote.  The Project Scientist(s) will have the following substantial involvement:

• Participating with the other SCORCH Program Steering Committee members in addressing issues that arise with SCORCH planning, operation, assessment, and data analysis. The Project Scientist(s) will assist and facilitate the group process and not direct it.
• Serving as a liaison, helping to coordinate activities, including acting as a liaison to other NIH Institutes/Centers, and as an information resource for the awardees. The Project Scientist(s) will also help coordinate the efforts of the SCORCH Consortium with other groups conducting similar efforts.
• Attending all SCORCH Program Steering Committee meetings as a voting member, assisting in developing standard operating procedures, and consistent policies for dealing with situations that require coordinated action. The Project Scientist(s) will be responsible for working with the grantees as needed to manage the logistic aspects of the SCORCH program.
• Reporting periodically on SCORCH progress to the NIH SCORCH Working Group.
• Serving on subcommittees of the SCORCH Program Steering Committee as appropriate.
• Assisting awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
• Providing advice in the management and technical performance of the award.
• Assisting in promoting the availability of the data and related resources developed by the SCORCH program to the scientific community at large. 
• Participating in data analyses, interpretations, and where warranted, co-authorship of the publication of results of studies conducted through the program. 
• Other NIH SCORCH Working Group staff may assist the awardee as designated by the Program Official.

Additionally, an agency Program Official or IC Program Director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned Program Official may also serve as an NIH Working Group Project Scientist(s) to assist the awardee. Prior to funding an application, the Program Official will contact the applicant to discuss the proposed milestones and any changes suggested by NIH staff or the NIH review panel. The Program Official and Project Scientist will negotiate with the applicant and agree on a final set of approved milestones which will be specified in the Notice of Award. The NIH Program Official, in consultation with the Project Scientist and NIH SCORCH Working Group, will determine if the awardee has met the milestones required for each year of funding.

NIH reserves the right to withhold funding or curtail an award in the event of:

• Substantive changes in the project, or failure to make sufficient progress toward the work scope with which NIH concurred, or
• Ethical or conflict of interest issues.

Areas of Joint Responsibility include:

• Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, to manage and assess the SCORCH program. The awardees and the Project Scientist(s) will meet in person with the SCORCH Program Steering Committee yearly and on conference calls as needed to share information on methodologies, analytical tools, and preliminary results. PDs/PIs, key co-investigators and pre- and post-doctoral trainees, especially those who are members of under-represented minority groups or those from different but related disciplines, are eligible to attend these meetings.
• The SCORCH Program Steering Committee will serve as the main scientific body of the program.  The SCORCH Program Steering Committee will be responsible for coordinating the activities being conducted by the program and is the committee through which the NIH SCORCH Working Group formally interacts with the SCORCH investigators. The SCORCH Program Steering Committee membership will include PD(s)/PI(s) of each SCORCH award, other staff as needed (ex-officio) and the NIH Project Scientist(s). The SCORCH Program Steering Committee may add additional members, and other government staff may attend the SCORCH Program Steering Committee meetings as desired. Each project will have one vote and the NIH Program Scientist(s) together will have one vote.
• The SCORCH Program Steering Committee may establish subcommittees as needed to address particular issues, which will include representatives from the program and the NIH and possibly other experts. The SCORCH Program Steering Committee will have the overall responsibility of assessing and prioritizing the progress of the various subcommittees.

The SCORCH awardee agrees to work collaboratively to:

• Provide for secure, accurate and timely data submission.
• Participate in presenting and publishing new processes and substantive findings.
• Assess and disseminate SCORCH data and resources
• Participate in the governance of the SCORCH program as a member of the SCORCH Program Steering Committee.
• Interact with other relevant NIH activities, as needed, to promote synergy and consistency among similar projects.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. The three members will be: a designee of the SCORCH Program Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

John Satterlee, Ph.D. 
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1020
Email: satterleej@nida.nih.gov

Nuria Assa-Munt. Ph.D.
Center for Scientific Review
Telephone: 301-451-1323
Email: assamunu@mail.nih.gov

Aida Vasquez 
National Institute on Drug Abuse (NIDA)
Telephone: 301-480-2154
Email: vasquez@mail.nih.gov 

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

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 Part 52 and 45 CFR Part 75.