Introduction

This funding opportunity announcement (FOA) aims to promote innovative research across multiple disciplines to increase knowledge of understudied non-olfactory G protein-coupled receptors (GPCRs), ion channels, and protein kinases. The submission of small research (R03) applications is encouraged from institutions and organizations proposing projects leading to a better understanding of eligible proteins identified as understudied by the Common Fund Program "Illuminating the Druggable Genome" (IDG; https://commonfund.nih.gov/idg/index).

Small research (R03) grants provide flexibility for initiating discrete, well-defined projects that realistically can be completed in one year and require limited levels of funding. This program supports different types of projects including, but not limited to, the following:

• Pilot or feasibility studies;
• Small, self-contained research projects;
• Development of research methodology; and/or
• Development of new research technology.

The award will support generation of preliminary data around eligible understudied protein(s) identified by the IDG with the intent of producing new knowledge and obtaining sufficient preliminary/validation data for subsequent R01 applications or drug discovery projects. These grants are non-renewable.

This initiative is funded through the NIH Common Fund, which supports cross-cutting programs that are expected to have exceptionally high impact. All Common Fund initiatives invite investigators to develop bold, innovative, and often risky approaches to address problems that may seem intractable or to seize new opportunities that offer the potential for rapid progress.

This Funding Opportunity Announcement does not accept applications proposing clinical trial(s).

Background

The human genome has revealed a great deal about the human proteome, though significant portions remain understudied. Only a subset of expressed proteins demonstrates 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 genes in the human genome encoding proteins 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 3,000, the existing clinical pharmacopeia is represented by only a few hundred targets, leaving a huge swath of biology that remains unexploited.

The discovery of a disease association or the development of a useful tool or reagent can accelerate research into a previous understudied protein, such as was the case for BRAF. Thus, while many interesting and critical biological processes and potential therapeutic avenues remain unexplored because an initial, catalyzing event has not yet occurred, the IDG Program will address this bottleneck by systematically querying these understudied proteins to find phenotypic associations and develop useful research tools.

While at the informatics level, genome-, and proteome-wide tools can collate information and query all proteins, technical feasibility necessitates a narrower focus of experimental efforts into protein families for which there are definable understudied members along with existing technologies that can be readily adapted at the scale necessary for wholesale elucidation of their function and generation of tools. During the Pilot Phase of the IDG, it was determined that the experimental focus of the IDG program will be on the understudied members in the families of non-olfactory GPCRs, ion channels, and protein kinases, as these families contain adequate numbers of understudied members and are well-established druggable families with high potential to impact human health once disease associations are made. It is expected that experimental priorities of the proteins within these three families will change over the period of the IDG program.

The IDG Consortium is expected to transform research by revealing a number of new activities and potential drug targets amongst these understudied proteins. Moreover, it is anticipated that the IDG Consortium will enhance our understanding of on- and off-target effects by establishing functional relationships among understudied members of the commonly targeted protein families.

Thus, the overall long-term goals of the IDG Program are two-fold:

• To advance research through the development, broad dissemination, and use of community scientific resources to study human proteins for which publicly available information or active research is lacking in order to catalyze the discovery of novel biology, with a particular focus on understudied members of the protein kinase, ion channel, and non-olfactory GPCR families.
• To demonstrate the feasibility and benefits of illuminating the roles of understudied proteins, permitting the expansion of such approaches to a broader array of protein families beyond the three families of proteins in the IDG Program.

To accomplish these goals, awardees of this FOA will be working closely with the existing awardees in the IDG program in the generation of new knowledge and testing of tools and reagents. Awardees from all IDG FOAs will form the nucleus of the IDG Consortium that will pursue the overall goals of the program. Additional non-IDG-funded members could be included in the IDG Consortium in the future.

The current IDG Consortium is made up of awardees from the following FOAs:

• The Knowledge Management Center (KMC; RFA-RM-16-024) aggregates knowledge from a protein-centric viewpoint across the entire human proteome, with an emphasis on the understudied non-olfactory GPCRs, protein kinases, and ion channels that are the focus of the experimental initiative. The KMC develops a knowledge portal (Pharos) that includes the aggregated data and metadata, a query interface, and deployed informatics tools along with community access to resources developed by the IDG Consortium. The main goal of Pharos is to provide access to aggregated data and IDG resources for the broad scientific community.
• The Data and Resource Generation Centers (DRGCs; RFA-RM-16-026) generate and validate new knowledge and/or tools relevant to the understudied members of the protein kinase, ion channel, and non-olfactory GPCR families with the intent of broadly and rapidly disseminating knowledge and tools to the research community. As one of the essential goals of this program, NIH intends that tools and reagents generated by the IDG Consortium will be broadly available and distributed at minimal cost, and without undue intellectual property constraints, so that they can be used as widely as possible, enabling further investigation of understudied proteins by the larger scientific community.
• The Resource Dissemination and Outreach Center (RDOC; RFA-RM-16-025) assists in the dissemination of data and tools and the overall coordination of the IDG Consortium. The IDG RDOC works with all IDG Consortium investigators to collect, curate, and disseminate information regarding critical tools and reagents being developed by the IDG Consortium through the IDG Portal.
• Cutting Edge Informatics Tools (CEITs; RFA-RM-18-011) are intended to add to the informatics capabilities of the IDG program. These new tools will augment the capability of the KMC as well as the broader IDG Consortium in the following ways: (1) by developing and deploying tools to enhance the community's ability to process, analyze, and visualize IDG data, (2) to prioritize new data resources and methods to be incorporated into Pharos that will strengthen predictions about physiological and disease associations around the understudied proteins, and (3) by developing methods to prioritize understudied IDG families (non-olfactory GPCRs, protein kinases, and ion channels) for deeper study using experimental assays both within the IDG pipeline or by the larger community.

Objectives and Scope

The goal of this FOA is to fund pilot projects on IDG-eligible understudied proteins beyond what the IDG’s Centers can accomplish, and/or to validate and demonstrate the utility of IDG reagents, data, and approaches. Specifically, this FOA supports small research projects that focus on pilot/validation studies associated with understudied protein(s) (IDG-eligible proteins; ion channels, GPCRs, and protein kinases) that are of interest to the IDG consortium. These projects should be carried out in a short period of time with limited resources.

Multiple community workshops held during the pilot phase of the IDG program concluded that understudied proteins become illuminated when (1) there are tools to study the protein (e.g., tools that modulate protein activity) and (2) there is biochemical, cellular, or animal model evidence of disease/physiological relevance. This FOA was developed to address the need for expanded research and validation experiments on IDG-identified understudied protein(s), with the intent of producing preliminary data to address the lack of biochemical, cellular, or animal model data associated with many IDG-eligible proteins. IDG-eligible proteins have low Jensen and PubTator Scores and minimal or no R01s.

IDG-eligible proteins open for study under this FOA:

Kinases

ADCK1, ADCK2, ADCK5, ALPK2, ALPK3, BCKDK, CAMK1D, CAMK1G, CAMKK1, CAMKV, CDC42BPB, CDC42BPG, CDK10, CDK11B, CDK14, CDK15, CDK17, CDK18, CDKL1, CDKL2, CDKL3, CDKL4, CLK3, CLK4, COQ8A, COQ8B, CSNK1G1, CSNK1G2, CSNK1G3, CSNK2A2, DSTYK, DYRK1B, DYRK2, DYRK3, DYRK4, EEF2K, ERN2, HIPK4, LMTK3, LRRK1, LTK, MAP3K10, MAP3K14, MAPK15, MAPK4, MARK4, MAST2, MAST3, MAST4, MKNK2, NEK10, NEK11, NEK4, NEK5, NEK6, NEK7, NIM1K, NRBP2, NRK, PAK3, PAK5, PAK6, PAN3, PDIK1L, PHKG1, PHKG2, PI4KA, PIK3C2B, PIK3C2G, PIP4K2C, PIP5K1A, PIP5K1B, PKMYT1, PKN3, PNCK, POMK, PRAG1, PRKACB, PRKACG, PRKCQ, PRPF4B, PSKH1, PSKH2, PXK, RIOK1, RIOK2, RIOK3, RPS6KC1, RPS6KL1, SBK1, SBK2, SBK3, SCYL1, SCYL2, SCYL3, SGK494, SRPK3, STK17A, STK3, STK31, STK32A, STK32B, STK32C, STK33, STK36, STK38L, STK40, STKLD1, TBCK, TESK1, TESK2, TLK1, TLK2, TP53RK, TSSK1B, TSSK3, TSSK4, TSSK6, TTBK1, TTBK2, ULK4, VRK2, VRK3, WEE2, WNK2

Ion Channels

ASIC4, BEST4, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1, CACNB2, CACNB3, CACNB4, CACNG1, CACNG3, CACNG4, CACNG5, CACNG6, CACNG7, CACNG8, CATSPER2, CHRNA10, CHRNA2, CHRNB1, CHRND, CLCA2, CLCA4, CLCC1, CLCN6, CLCNKA, CLIC2, CLIC3, CLIC5, CLIC6, CNGA4, FAM26D, FAM26E, FAM26F, FXYD3, FXYD7, GABRG1, GABRP, GABRR1, GLRA3, GLRA4, GLRB, GPR89A, GPR89B, GRID1, GRIK3, HTR3C, HTR3D, HTR3E, KCNA6, KCNA7, KCNAB2, KCNAB3, KCNC4, KCND1, KCNG2, KCNG3, KCNG4, KCNH4, KCNH6, KCNH8, KCNIP1, KCNIP4, KCNJ14, KCNJ15, KCNJ18, KCNK12, KCNK4, KCNK7, KCNMB3, KCNMB4, KCNN1, KCNS1, KCNS2, KCNS3, KCNT1, KCNT2, KCNV1, LRRC38, LRRC55, PANX2, PKD1L2, PKD1L3, PKD2L2, PLLP, SCN2B, SCN3B, SCN7A, SCNN1B, SCNN1D, SLC26A1, TMC3, TMC4, TMC5, TMC7, TMEM38B, TMEM63A, TMEM63B, TMEM63C, TTYH1, TTYH2

GPCRs

ADGRA1, ADGRB2, ADGRB3, ADGRD1, ADGRD2, ADGRE1, ADGRE2, ADGRE3, ADGRF1, ADGRF2, ADGRF3, ADGRF4, ADGRF5, ADGRG2, ADGRG3, ADGRG4, ADGRG5, ADGRG7, FZD10, GNRHR2, GPR101, GPR12, GPR135, GPR137, GPR139, GPR141, GPR142, GPR143, GPR146, GPR149, GPR150, GPR151, GPR152, GPR153, GPR156, GPR157, GPR160, GPR162, GPR171, GPR173, GPR174, GPR18, GPR19, GPR20, GPR21, GPR22, GPR25, GPR26, GPR27, GPR31, GPR32, GPR32P1, GPR34, GPR37L1, GPR39, GPR4, GPR45, GPR50, GPR52, GPR6, GPR61, GPR62, GPR63, GPR68, GPR75, GPR78, GPR82, GPR85, GPR87, GPR88, GPRC5A, GPRC5B, GPRC5C, GPRC5D, HCAR1, HCAR3, LPAR6, MAS1L, MRGPRE, MRGPRF, MRGPRG, MRGPRX2, MRGPRX3, MRGPRX4, NPBWR1, NPBWR2, NPY2R, NPY5R, OXER1, OXGR1, P2RY10, P2RY11, PROKR1, QRFPR, RXFP3, RXFP4, SUCNR1, TAAR2, TAAR3, TAAR8, TAAR9, TPRA1

This FOA accepts different types of projects with the intent of generating preliminary/validation data for subsequent funding including, but not limited to, the following:

• Isolation and purification of understudied proteins and initial in vitro characterization;
• Development of accessory reagents (e.g., antibodies, peptide fragments, labeled versions of the protein, etc.) for use in downstream studies to generate preliminary data;
• Assay development, optimization, and validation with the intent of using these assays for further study of selected understudied protein(s);
• Validation or placement of understudied protein(s) in signaling cascades, including upstream signals and downstream activities;
• Characterization of cell- and tissue-specific protein expression, localization, and function of understudied protein(s) in native environments;
• Use of data mining and experimental validation to analyze IDG-generated data sets and other public data resources to identify and study protein-protein interaction networks or generate hypotheses about the function of understudied protein(s);
• Use of IDG-generated (or other) 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);
• Experimental validation of predictive protein models produced by the IDG;
• Structure determination or preparation of understudied proteins for structure determination and characterization by x-ray crystallography, cryo-electron microscopy, or similar approaches.

All relevant datasets and capabilities associated with understudied proteins collected by the IDG can be found in Pharos. Applicants are strongly encouraged to use available resources in Pharos when applying to this FOA as part of the justification for the approach selected and/or to assist in accomplishing the goals of the project. Applicants should also review DruggableGenome, the IDG Consortium website, to explore available tools developed by the IDG Consortium and to ensure proposed work does not overlap with ongoing studies being performed by the IDG Consortium.

The following will be considered non-responsive and these applications could be withdrawn:

• Projects that meet the NIH definition of a clinical trial;
• Projects where the majority of proposed work focuses on proteins outside of those listed above;
• Applications that propose clinical drug development studies for IDG-eligible protein(s);
• Any approach that does not primarily focus on elucidating the function of IDG-eligible understudied proteins;
• Projects that propose work identical to that currently being performed by the IDG Consortium (consult DruggableGenome for IDG Consortium current projects).

The applicant should have sufficient information to give confidence to the reviewers that the proposed work is feasible, and that data derived from the project would likely be suitable as preliminary/validation data for a subsequent R01 application or drug discovery project. Applicants should identify the IDG-eligible protein(s) they propose to study and indicate how their project will help to elucidate the function of the understudied protein(s). Projects should help to elucidate the function and/or structure of the understudied protein(s) in relevant models that will ultimately inform human conditions. Consistent with achieving the goals of this program, the NIH expects that information such as collected data, technical protocols, and any other metadata collected under this FOA is to be made accessible via Pharos.

It is important to note that modeling and informatics activities within the IDG consortium are not necessarily meant for starting drug discovery and development projects. At this point, most activities will be focused on finding the role of understudied proteins in physiology and disease, identifying relevant pathways, or identifying ligands or other modulators. Proposed studies must be applicable to at least one protein from the above list of IDG-eligible proteins.

Frequently Asked Questions regarding this FOA will be posted on the Common Funds IDG website. Applicants are encouraged to review the FAQs prior to submitting their applications.

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

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. 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.

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)

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

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. The Plan should include how the data will be shared through Pharos, the type of data to be shared, and the timeline for sharing data.
• Consistent with achieving the goals of this program, the NIH expects that information such as collected data, technical protocols, and any other metadata collected under this FOA is to be made accessible via Pharos. Data should be submitted to an appropriate repository and this information provided to the Resource Dissemination and Outreach Center (RDOC) consistent with the IDG Consortium's data sharing policy.
• If applicable, applicants must abide by the NIH Genomic Data Sharing Policy (https://osp.od.nih.gov/scientific-sharing/genomic-data-sharing/) and should indicate their agreement to it, e.g., in the data sharing plan.
• Applicants should also be familiar with the NIH statements regarding intellectual property of resources developed with Federal funds (NIH Research Tools Policy (http://grants.nih.gov/grants/intell-property_64FR72090.pdf) and other related NIH sharing policies at http://sharing.nih.gov).
• Prior to funding, NIH Program Staff may negotiate modifications to the Sharing Plan with the applicant.

Only limited Appendix materials are allowed.

No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

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.

All instructions in the SF424 (R&R) Application Guide must be followed. 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. 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. 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. As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score. Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center for Scientific Review, 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.