Expired PAR-13-350: Early Career Award in Chemistry of Drug Abuse and Addiction (ECHEM) (R21/R33)

Part 1. Overview Information

Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute on Drug Abuse (NIDA)
Funding Opportunity Title	Early Career Award in Chemistry of Drug Abuse and Addiction (ECHEM) (R21/R33)
Activity Code	R21/R33 Phased Innovation Award
Announcement Type	Reissue of PAS-10-274
Related Notices	August 1, 2016 - This PAR has been reissued as PAR-16-384. NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015) March 17, 2015 - Notice of Correction to the Individual Eligibility for PAR-13-350. See Notice NOT-DA-15-044. June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
Funding Opportunity Announcement (FOA) Number	PAR-13-350
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.279
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) seeks to facilitate the entry of new-to-NIH investigators into basic chemistry research applied to drug abuse and addiction.

Key Dates

Posted Date	September 11, 2013
Open Date (Earliest Submission Date)	September 16, 2013
Letter of Intent Due Date(s)	Not Applicable
Application Due Date(s)	Standard dates apply, by 5:00 PM local time of applicant organization. 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)	Standard AIDS dates apply by 5:00 PM local time of applicant organization. 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.
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	New Date August 1, 2016 per issuance of PAR-16-384. (Original Expiration Date: September 8, 2016)
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the 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.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

This Funding Opportunity Announcement (FOA) seeks to facilitate the entry of new-to-NIH investigators into basic chemistry research applied to drug abuse and addiction.

Background

NIDA-funded research has furthered our understanding of the neurobiological mechanisms underlying drug addiction, but much remains to be learned. In particular, there is a need for research in the basic biological and chemical sciences to identify and explicate the neural mechanisms underlying drug abuse and addiction. Research into the chemistry of drug abuse can identify new targets for interventions or new chemical templates for treating toxic side effects of drugs/drugs of abuse. Moreover, the development of appropriate probes or new technologies has the potential to advance the field at a rapid rate. The study of the genetic, molecular, cellular, circuit-based, and behavioral mechanisms involved in addiction and the development of associated therapeutic strategies may all benefit from synthetic chemical research and approaches.

To date, NIDA grantees have synthesized a number of ligands, targeting a wide variety of targets for several different research purposes. Ligands have been developed, for example, that target receptors, transporters, ion channels and enzymes by which drugs of abuse have been shown to interact; multiple structural analogs have been synthesized including ligands that have been shown to possess dual functions (e.g., mu agonist-delta antagonist); and, imaging agents have been synthesized that target both transporters and receptors (e.g., [11C] RTI-121 as a selective radioligand for PET studies of the dopamine transporter). Yet, there remains a need to develop new research probes or therapeutic compounds that are specific and efficacious.

Objectives

This announcement is intended to encourage early career chemists (or chemists new to NIH) to develop probes that aid basic research investigations on drug abuse and/or identify new or better templates as lead compounds with potential for conducting structure activity relationship (SAR)-function studies. Importantly, this includes the identification of new chemical entities (NCEs) with therapeutic potential for drug abuse and addiction. Applicants responding to this FOA should explain their rationale for the proposed work, the inclusion of pharmacologic assessments, and the relationship of the research proposed in the context of a broader medications development pipeline (e.g., Target Identification > Probe/ligand screening > Synthesis of ligands > Assay development > Proof of concept > Lead optimization, etc.).

Nevertheless, appropriate theoretical justification and sound hypotheses should be provided to engender confidence that the project is well thought out and feasible. Researchers interested in seeking funding for developmental research projects within the later stages of medications development, especially those not new to NIH who may already have preliminary data, are referred to other announcements such as PAR-13-270 entitled, "Grand Opportunities in Medications Development .

An R21/R33 Phased Innovation Award has two phases: (1) R21 for milestone-driven exploratory or feasibility studies with a possible transition to, (2) the R33 for expanded development.

Transition to the R33 depends on the ability of the applicant to meet predefined milestones (which are evaluated in peer review and negotiated with NIDA Scientific/Research Contract prior to the R21 award), as well as program priorities and the availability of funds. NIDA anticipates that a maximum of 50%-70% of the funded R21 phase awards will progress to the R33 award.

There are four research areas of particular interest for this FOA as follows:

1. Development of new and innovative molecular probes/ligands for receptors, transporters, ion channels, enzymes or other justifiable neurobiological targets associated with drug addiction and pain. Specific targets of interest include, but are not limited to:

a3/a5 nicotinic acetylcholine receptor,
Cannabinoid receptors (e.g., CB1 receptor antagonists), or cannabinoid-like receptors
Corticotropin-releasing factor (CRF-1) receptor (e.g., CRF-1 antagonists),
Dopamine D1-type receptors (e.g., D1 receptor agonists),
Dopamine D2-type receptors (e.g., D3 receptor agonists or antagonists),
GABA receptors (e.g., GABA-B receptor agonists),
mu-, kappa-, or delta-opioid receptors,
Nociception (ORL-1) receptor (e.g., ORL-1 receptor agonists),
Glutamate receptor modulators (e.g., mGluR5 antagonists),
Muscarinic M5 acetylcholine receptor,
Orexin (hypocretin) receptor modulators (type 1 or 2),
Serotonin receptor modulators (e.g., 5-HT2C receptor agonist),
Histone deacetylases (HDACs), or
Transient receptor potential (TRP) channels.

All SAR projects that might ultimately aid in the development of new probe/potential drug synthesis and/or aid in the understanding of neurochemical mechanisms of drug addiction are important areas of research under this FOA. Research aimed at the development of novel receptor-specific antagonists, agonists, partial agonists, negative and/or positive allosteric modulators, or the identification of pharmacophores for potential drug design would all be responsive projects. See also the NIDA Addiction Treatment Discovery Program Guide for Compound Submitters for additional possibilities.

2. The development of novel ligands for use in neuroimaging studies of addiction issought. New PD/PIs are needed who have the potential to develop novel radioligands for positron emission tomography (PET) and/or single photon emission computed tomography (SPECT) imaging in human brain. These radiotracers can be tested initially in preclinical models, but ideally would be used for clinical neuroimaging as potential biomarkers (e.g., PET ligands for receptors, ion channels, enzymes, transporters, etc.).

3. The application of newer areas of research, and their associated technologies. This would include areas such as genomics, transcriptomics (e.g., microarrays), proteomics, metabolomics, or lipidomics in the discovery and identification of new endogenous ligands that play a role in the underlying mechanisms of substance use disorders (SUDs). Data from these projects could be used for the identification and/or development of a diagnostic biomarker associated with drug dependence, or, perhaps, could include the development of a pharmacodynamic biomarker associated with (or ideally predictive of) a potential treatment outcome (good or bad) for drug dependence.

4. Research projects aimed at isolating, identifying, purifying and characterizing new lipid ligands, receptors, transporters, enzymes, etc. for the cannabinoid, vanilloid or other lipid-based targets, would also be supported.

Some examples of research topics are provided below. These are NOT intended to be exclusionary or exhaustive. Applicants are strongly encouraged to contact program staff to discuss proposed studies or to obtain clarification.

Discovery

Development of receptor-subtype-specific ligands that aid basic research investigations on drug abuse, especially those with reduced risk for addiction.
Identify new or better templates as lead compounds with potential for conducting SAR-function studies.
Isolation and identification of new chemical metabolites and characterization of their biological activity.
Isolation and characterization of bioactive chemicals from plants and other natural products that may be relevant to drug abuse research.
Isolation and characterization of endogenous receptor ligands and their biosynthetic enzymes.
Structural biological studies of homo- and/or heteromeric receptors that may help to elucidate underlying mechanisms of addiction.

Synthesis

Design and synthesis of HDAC inhibitors to elucidate the role of HDACs in SUDs.
Synthesis of novel receptor subtype-specific ligands, allosteric modulators, or dual-specific ligands; ligands may be for any sort of target (G-protein coupled receptor/ion channels, transporters, enzymes, etc.) that have a strong mechanistic role in potential underlying mechanism(s) of addiction.
Synthesis of biological probes/tools to better understand and track the various stages of drug addiction from initial use, to misuse, abuse, dependence, withdrawal, and ultimately relapse.
Synthesis of biological probes to investigate the mechanisms of toxicity of drugs of abuse or probes that may serve as lead compounds for drug/ligand design and synthesis of agents that prevent or mitigate toxicity based on known mechanisms or newly proposed mechanisms.
Synthesis of new and improved imaging agents to aid in receptor mapping or to correlate biological/behavioral patterns to biological substrates; imaging agents that are receptor subtype-specific/transporter-specific (e.g., mu-opioid, DAT, hypocretin [HCrt1; orexin] receptor, etc.) may also be considered.
Strategies for innovative peptidomimetic design; synthesis of stable peptides.

Probe and ligand development

Development of specific ligands for homo- and heteromeric receptors, demonstration of interaction modalities and stereochemistry, identification of key structural elements for interaction.
Development of probes to study potential for receptor/transporter dimerization, SAR of dimerization.
Development of biological probes based on natural products and SAR studies on analogs.
Development of VMAT2 or related ligands as probes for stimulant abuse.
Development of ligands for orphan receptors to study their SAR, and elucidate their role in addiction pathways or pain.

Assays and Screens for Validation Studies

Methodologies to study homo- and heteromers of receptors/transporters for mechanistic and biophysical studies of targets that are likely to be involved in mechanisms of addiction or pain.
Kinase inhibitors or other molecules that modulate signal transduction mechanisms; other molecular entities that play a role in regulating GPCRs; enzyme regulators that modulate the function of receptors, transporters or other cellular targets shown to be involved in processes of addiction.
Improved, specific cell based high throughput assays for identification of new ligands for receptors, transporters, enzymes, etc.

Lead Optimization & Delivery

Recombination of synthesized peptides/proteins/pharmacotherapies into nanocapsules (or other delivery vehicles) to facilitate, stabilize and extend molecular release of a treatment in an effort to improve treatment adherence/compliance.
New approaches/strategies to synthesize analgesics without side effects and have limited potential for diversion/abuse.
Development of innovative nanotechnologies for targeted drug delivery, delivery of peptidomimetics, technologies that enhance transport to the CNS.
Development of innovative nanotechnologies for the development of novel extended release formulations for biologics or pharmacotherapeutics (e.g., microgels, nanoparticles) that would significantly enhance medication adherence /compliance.

Structural Studies

Determination of 3D biophysical structure of receptors, transporters, ion channels, enzymes, transmembrane helices, segments of helices that regulate interaction with ligands, extra- and intracellular loops, as well as protein-ligand binding interactions.

Computational modeling

Use of human genetic variant data or epigenetic data to map or identify potential protein conformations that affect ligand binding, receptor signaling, receptor cycling, etc.
Biophysical and computational/modeling studies to aid in the design of the ligands classes described above and for not-yet fully characterized transport and other systems.

Special Considerations

HIV/AIDS Counseling and Testing Policy for the National Institute on Drug Abuse: In light of recent significant advances in rapid testing for HIV and in effective treatments for HIV, NIDA has revised its 2001 policy on HIV counseling and testing. NIDA-funded researchers are strongly encouraged to provide and/or refer research subjects to HIV risk reduction education and education about the benefits of HIV treatment, counseling and testing, referral to treatment, and other appropriate interventions to prevent acquisition and transmission of HIV. This policy applies to all NIDA funded research conducted domestically or internationally. For more information see http://grants.nih.gov/grants/guide/notice-files/NOT-DA-07-013.html.

National Advisory Council on Drug Abuse Recommended Guidelines for the Administration of Drugs to Human Subjects: The National Advisory Council on Drug Abuse (NACDA) recognizes the importance of research involving the administration of drugs with abuse potential, and dependence or addiction liability, to human subjects. Potential applicants are encouraged to obtain and review these recommendations of Council before submitting an application that will administer compounds to human subjects. The guidelines are available on NIDA's Web site at http://www.drugabuse.gov/funding/clinical-research/nacda-guidelines-administration-drugs-to-human-subjects.

Points to Consider Regarding Tobacco Industry Funding of NIDA Applicants: The National Advisory Council on Drug Abuse (NACDA) encourages NIDA and its grantees to consider the points it has set forth with regard to existing or prospective sponsored research agreements with tobacco companies or their related entities and the impact of acceptance of tobacco industry funding on NIDA's credibility and reputation within the scientific community. Please see http://www.drugabuse.gov/about-nida/advisory-boards-groups/national-advisory-council-drug-abuse-nacda/council-statements/points-to-consider-regarding- for details.

Data Harmonization for Substance Abuse and Addiction via the PhenX Toolkit: NIDA strongly encourages investigators involved in human-subjects studies to employ a common set of tools and resources that will promote the collection of comparable data across studies and to do so by incorporating the measures from the Core and Specialty collections, which are available in the Substance Abuse and Addiction Collection of the PhenX Toolkit (www.phenxtoolkit.org). Please see NOT-DA-12-008 (http://grants.nih.gov/grants/guide/notice-files/NOT-DA-12-008.html) for further details.

Section II. Award Information

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New Resubmission Revision The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
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.
Award Budget	For the R21 award, direct costs are limited to $250,000 over a two-year period, with a maximum of $200,000 allowed in any single year. The R33 award will be limited to $250,000 in direct costs per year.
Award Project Period	The total project period may not exceed 4 years. Awards will support milestone-driven exploratory/feasibility proof of concept studies (R21 phase, up to two years), with possible rapid transition to expedited development (R33 phase, up to three years, depending upon the requested period for the R21 phase).

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

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:

Hispanic-serving Institutions
Historically Black Colleges and Universities (HBCUs)
Tribally Controlled Colleges and Universities (TCCUs)
Alaska Native and Native Hawaiian Serving Institutions
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)

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.

Required Registrations

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) (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.
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 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 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 and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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 Investigator)

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 is intended to encourage early career chemists (or chemists new to NIH) to develop probes that aid basic research, discovery and early development on drug abuse and/or identify new or better templates as lead compounds with potential for conducting SAR-function studies.

A New Investigator is an NIH research grant applicant who may not yet have competed successfully for a substantial, NIH research grant. For example, a PD/PI who has previously received a competing NIH R01 research grant is no longer considered a New Investigator. However, a PD/PI who has received a small grant (R03) or an Exploratory, Developmental Research Grant Award (R21) retains his or her status as a New Investigator. For a complete list of NIH grants that do not disqualify a PD/PI from being considered a New Investigator, please see: http://grants.nih.gov/grants/new_investigators/index.htm.

An ESI, or Early Stage Investigator, is a New Investigator who has completed his or her terminal research degree or medical residency whichever date is later within the past 10 years and has not yet been awarded a substantial, competing NIH research grant. The dates that start the period of classification as an Early Stage investigator are entered in the investigators eRA Commons Profile (https://commons.era.nih.gov/commons/).

If the PD/PI no longer meets the NIH definition of an ESI or an NI (as above), the PD/PI would still be eligible to apply to this FOA. To encourage the funding of early-career chemists (or chemists new to NIH), ESI or NI's will receive funding priority over more established investigators.

It is expected that ESIs will constitute the majority of funded NIs. Software within the eRA Commons will check first for New Investigator status based on the individual’s previous award history. A New Investigator is identified in the NIH eRA Commons by searching for evidence of previous substantial research grant awards. ESIs are identified in the eRA Commons based on information entered about degree conferral date or the end of residency date, whichever is most recent. (Updated March 17, 2015 per issuance of NOT-DA-15-044.)

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

Required and Optional Components

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

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 application to this FOA.

SF424(R&R) Cover