This Notice is part of the NIH Helping to End Addiction Long-Term (HEAL) Initiative, an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis.

NCATS and other participating institutes and Centers (ICs) are inviting investigators with relevant active research project grants and cooperative agreements to submit administrative supplements, according to PA-18-591 Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional), for funded projects to identify and validate new pain and opioid use disorder (OUD) targets from within the understudied Druggable Genome.

Background:

The human genome has revealed a great deal about the human proteome, though significant portions of the genome remain understudied. Only a subset of expressed proteins demonstrate the requisite properties to serve as targets for the development of therapeutics. Many bona fide drug targets likely remain to be discovered in the Druggable Genome (DG), which can be defined as a subset of the ~20,000 protein-coding genes in the human genome that have the potential to bind drug-like molecules. The term "drug-like" refers to the physical, biochemical, and pharmacological attributes of small molecule compounds that are generally recognized to be required for efficacious clinical drugs in humans. While the number of proteins in the DG is upwards of 4,500, the existing clinical pharmacopeia is represented by only a few hundred targets, leaving a huge swath of biology that remains unexploited.

This announcement is for one-year administrative supplements to ongoing funded projects to support research that will identify and validate new targets for pain and OUD among the understudied proteins of the Druggable Genome. Kinases such as ERK1/2, p38 and JNK have been shown to counteract opioid analgesia and precede desensitization of the opioid receptors. In addition, opioid receptors belong to the well-known Gi/o class of GPCRs, and GPCRs have been shown to mediate pain and neurogenic inflammation. Finally, many ion channels have been identified as critical elements in pain signaling and transmission. As these families contain adequate numbers of understudied members and are well established druggable families shown to be critical in pathways associated with pain and OUD, experimental focus will be placed on understudied members in the families of non-olfactory GPCRs, ion channels and protein kinases. Eligible understudied proteins listed below are considered understudied, as they meet the following criteria: the protein (1) has a low number of publications/citations, with a Jensen Pubmed score of <50 and (2) has minimal or no NIH funding.

Understudied proteins eligible for research support under this notice:

Kinases

ADCK1, ADCK2, ADCK5, ALPK2, ALPK3, BCKDK, BRSK1, CAMK1D, CAMK1G, CAMKK1, CAMKV, CDC42BPA, CDC42BPB, CDC42BPG, CDK10, CDK11A, CDK11B, CDK12, CDK13, CDK14, CDK15, CDK16, CDK17, CDK18, CDK19, CDK20, CDKL1, CDKL2, CDKL3, CDKL4, CLK3, CLK4, COQ8A, COQ8B, CSNK1A1L, CSNK1G1, CSNK1G2, CSNK1G3, CSNK2A3, DCLK3, DSTYK, DYRK1B, DYRK2, DYRK3, DYRK4, EEF2K, ERN2, HIPK1, HIPK3, HIPK4, ICK, LMTK2, LMTK3, LRRK1, LTK, MAP3K10, MAP3K14, MAP3K15, MAP3K21, MAPK15, MAPK4, MARK1, MARK3, MARK4, MAST2, MAST3, MAST4, MKNK2, NEK1, NEK10, NEK11, NEK3, NEK4, NEK5, NEK6, NEK7, NEK9, NIM1K, NRBP2, NRK, NUAK2, PAK3, PAK5, PAK6, PAN3, PDIK1L, PHKG1, PHKG2, PI4KA, PIK3C2B, PIK3C2G, PIP4K2C, PIP5K1A, PIP5K1B, PIP5K1C, PKMYT1, PKN3, PNCK, POMK, PRKACB, PRKACG, PRPF4B, PSKH1, PSKH2, PXK, RIOK1, RIOK2, RIOK3, RPS6KC1, RPS6KL1, SBK2, SBK3, SCYL2, SCYL3, SGK494, SRPK3, STK17A, STK17B, STK19, STK3, STK31, STK32A, STK32B, STK32C, STK33, STK36, STK38L, STK40, STKLD1, TAOK1, TAOK2, TBCK, TESK1, TESK2, TLK1, TLK2, TP53RK, TSSK1B, TSSK2, TSSK3, TSSK4, TSSK6, TTBK1, TTBK2, ULK4, VRK2, VRK3, WEE2, WNK2, WNK3

Ion Channels

ASIC4, BEST4, CACNA2D2, CACNA2D3, CACNA2D4, CACNG1, CACNG3, CACNG4, CACNG5, CACNG6, CACNG7, CACNG8, CALHM4, CALHM5, CALHM6, CATSPER2, CHRNA10, CHRNB1, CLCA4, CLCC1, CLCN6, CLIC6, GABRP, GPR89A, GPR89B, GRID1, KCNA6, KCNA7, KCNAB2, KCNAB3, KCND1, KCNG2, KCNG3, KCNG4, KCNH4, KCNH6, KCNH8, KCNJ15, KCNJ18, KCNK12, KCNK7, KCNMB3, KCNN1, KCNS1, KCNS2, LRRC38, LRRC55, PKD1L2, PKD1L3, PKD2L2, PLLP, SCN7A, SLC26A1, TMC3, TMC4, TMC5, TMC7, TMEM38B, TMEM63A, TMEM63B, TTYH1, TTYH2

G-Protein Coupled Receptors (GPCRs)

ADGRA1, ADGRA3, ADGRB2, ADGRB3, ADGRD1, ADGRD2, ADGRE1, ADGRE3, ADGRF1, ADGRF2, ADGRF3, ADGRF4, ADGRF5, ADGRG2, ADGRG3, ADGRG4, ADGRG5, ADGRG7, FZD10, GNRHR2, GPR101, GPR12, GPR135, GPR137, GPR139, GPR141, GPR142, GPR146, GPR149, GPR150, GPR151, GPR152, GPR153, GPR156, GPR157, GPR160, GPR162, GPR171, GPR173, GPR174, GPR18, GPR19, GPR20, GPR21, GPR22, GPR25, GPR26, GPR27, GPR3, GPR31, GPR32, GPR34, GPR37L1, GPR4, GPR45, GPR52, GPR6, GPR61, GPR62, GPR63, GPR65, GPR68, GPR75, GPR78, GPR82, GPR85, GPR87, GPR88, GPRC5A, GPRC5B, GPRC5C, GPRC5D, HCAR1, HCAR3, LPAR6, MRGPRE, MRGPRF, MRGPRG, MRGPRX1, MRGPRX2, MRGPRX3, MRGPRX4, NPBWR1, NPBWR2, OXER1, OXGR1, P2RY10, PROKR1, QRFPR, RXFP4, TAAR2, TAAR3P, TAAR8, TAAR9, TAS2R1, TAS2R10, TAS2R13, TAS2R14, TAS2R16, TAS2R19, TAS2R20, TAS2R3, TAS2R30, TAS2R31, TAS2R39, TAS2R4, TAS2R40, TAS2R41, TAS2R42, TAS2R43, TAS2R46, TAS2R5, TAS2R50, TAS2R60, TAS2R7, TAS2R8, TAS2R9

Examples of potential research areas include but would not be limited to:

• Isolation and purification of understudied proteins and in vitro/in vivo characterization with the intent of developing novel therapeutics;
• Validation or placement of understudied protein(s) in signaling cascades, including upstream signals and downstream activities in order to better understand pain and OUD targets;
• Pre-clinical animal studies of understudied Druggable Genome candidate proteins focused on therapeutic development and development of candidate therapeutics;
• Characterization of cell- and tissue-specific protein expression, localization, and function of understudied protein(s) in native environments as they pertain to pain and OUD;
• Use of novel tools to validate preliminary disease or physiological associations with understudied proteins in animal models, biomimetic systems, or ex vivo human samples;
• Studies to establish preliminary structure-activity-relationships (SAR) between functions of an understudied protein and its ligands (e.g., small molecules, macrocycles, synthetic peptides) for future drug discovery projects.

The work proposed must be within the scope of the existing award. Before submitting a supplement request, principal investigators are strongly encouraged to contact the appropriate IC contact listed at the end of this notice with any questions and to discuss whether the proposed supplement is within the scope of the parent award and consistent with the priorities of the IC supporting the parent award. Applications must include a detailed description of the proposed activities and a justification that the proposed work is within the scope of the existing award. Sufficient justification should be provided to indicate why particular protein(s) were chosen for study. Those projects employing methods that identify multiple proteins for study from the above lists are acceptable but require justification as to why those proteins were chosen, beyond the fact that they are on the eligible protein lists provided. Applications must also demonstrate adequate progress to date on the parent study.

The activities proposed in the supplement must be able to be accomplished within the current competitive segment.

Award Project Period

To be eligible, the parent award must be active in FY20 (i.e., the parent award received funds in FY20 and is not in an extension period), and the research proposed in the supplement should be requested for 1 year. The earliest anticipated start date is June 1, 2020.

Budget

Supplement budget requests cannot exceed $99,999 in direct costs (excluding subcontract F&A). Requests must reflect the actual needs of the proposed project. Requests may be for one year of support only. Modular and categorical budgets are permitted.

Eligible Individuals (Program Director/Principal Investigator)

Individual(s) must hold an active grant or cooperative agreement. For supplements to parent awards that include multiple PDs/PIs, the supplement may be requested by any or all of the PDs/PIs (in accordance with the existing leadership plan) and submitted by the awardee institution of the parent award

Application and Submission Information

Applications for this initiative must be submitted using the following opportunity or its subsequent reissued equivalent.

• PA-18-591 - Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)

All instructions in the SF424 (R&R) Application Guide and PA-18-591 must be followed, with the following additions:

Requests must be received by 5:00 PM local time of applicant organization on June 1, 2020 for funding in FY 2020.

• Application Due Date(s) June 1, 2020, by 5:00 PM local time of applicant organization.

• For funding consideration, applicants must include NOT-TR-20-008 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

• Requests may be for one year of support only. To be eligible, the parent award must be active in FY20 (i.e. applications in a no-cost extension are not eligible to apply.). The earliest anticipated start date is June 1, 2020.

• The Research Strategy section of the application is limited to 6 pages.

• The process for Streamlined Submissions using the eRA Commons cannot be used for this initiative.

• Applicants are strongly encouraged to notify the program contact at the Institute supporting the parent award that a request has been submitted in response to this FOA in order to facilitate efficient processing of the request.

• Supplement budget requests cannot exceed $99,999 in direct costs (excluding subcontract F&A) for one year. Requests must reflect the actual needs of the proposed project. Modular and categorical budgets are permitted

• Individual(s) must hold an active grant or cooperative agreement. For supplements to parent awards that include multiple PDs/PIs, the supplement may be requested by any or all of the PDs/PIs (in accordance with the existing leadership plan) and submitted by the awardee institution of the parent award.