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Extracellular RNA Communication

This program explores the impact of extracellular RNAs on human health and disease, focusing on the release, transport, uptake, and regulatory role of exRNAs in intercellular and inter-species communication. Funding opportunities are available for research on exRNA standards, reference profiles, fundamental biology principles, and clinical utility as biomarkers and therapeutic delivery vehicles.

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Extracellular RNA Communication

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  1. Extracellular RNA Communication

  2. Origins of the Common Fund 2004: NIH Roadmap is launched December 9, 2006: Congress unanimously passes a reauthorization bill affirming importance of NIH and its vital role in advancing biomedical research to improve the health of the Nation Establishes the Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI) within Office of the Director and theNIH Common Fund to provide a dedicated source of funding to enabletrans-NIH research

  3. Criteria for Common Fund Programs • Transformative: Must have high potential to dramatically affect biomedical and/or behavioral research over the next decade • Catalytic: Must achieve a defined set of high impact goals within 5-10 years • Synergistic: Outcomes must synergistically promote and advance individual missions of NIH Institutes and Centers to benefit health • Cross-cutting: Program areas must cut across missions of multiple NIH Institutes and Centers, be relevant to multiple diseases or conditions, and be sufficiently complex to require a coordinated, trans-NIH approach • Unique: Must be something no other entity is likely or able to do

  4. Current Common Fund Programs Extracellular RNA Communication NIH Common Fund Undiagnosed Diseases Program Molecular Libraries and Imaging Gulf Oil Spill Long Term Follow Up Health Economics PROMIS: Clinical Outcomes Assessment Regulatory Science NIH Center for Regenerative Medicine Human Microbiome Building Blocks, Biological Pathways And Networks Bridging Interventional Development Gaps (BrIDGs) NIH Medical Research Scholars Protein Capture Clinical Science and Translation Awards (CTSAs) Library of Integrated Network- Based Cellular Signatures (LINCS) Nanomedicine HCS Research Collaboratory High-Risk Research Knockout Mouse Phenotyping Global Health Pioneer Awards New Innovator Awards Transformative Research Awards Early Independence Awards Bioinformatics and Computational Biology Structural Biology Interdisciplinary Research Consortia Science of Behavior Change Metabolomics Genotype- Tissue Expression Epigenomics http://commonfund.nih.gov/ Single Cell Analysis

  5. Common Fund Strategic Planning Process Phase 1: Identification of broad topic areas that address the biggest challenges and greatest opportunities in biomedical research Phase 2: Refinement of broad areas into well-defined programs and initiatives *These are projects originating at a grass-roots level with scientists across all fields and/or from the institute/center directors at the NIH*

  6. Timeline of Common Fund Programs Strategic Planning Implementation Transition PHASE 1 PHASE 2 NEW PROGRAM 5-10 years > 10 years 18 months

  7. What makes a program Common Fund’able? Common Fund programs catalyze research across a broad spectrum of diseases/conditions • ■New Tools, Technologies, Data, Approaches • ■ Human Microbiome Project • ■ Library of Integrated Network-Based Cellular Signatures (LINCS) • ■ Patient Reported Outcomes Measurement Information System (PROMIS) • ■ Epigenomics • ■ Enabling Infrastructure • ■ Bridging Interventional Development Gaps (BrIDGs) • ■ Molecular Libraries and Imaging

  8. New FY 2013 program: Extracellular RNA Communication Opportunity to explore new paradigms of intracellular and inter-species communication based on the release, transport, uptake, and regulatory role of exRNAs What is the effect of Extracellular RNAs on human health and disease? Refs: Molec Cancer 2011, 10:117; Cell Res. Sept 2011, 1; Nat Biotech. 2011, 29(4):341.

  9. New FY 2013 program: Extracellular RNA Communication Opportunity to explore new paradigms of intercellular and inter-species communication based on the release, transport, uptake, and regulatory role of exRNAs Current Funding Opportunity Announcements: • RFA-RM-12-010: Establishment of a central repository for exRNA standards, protocols, and data • RFA-RM-12-011: Development of reference profiles for healthy human exRNAs in a variety of body fluids • RFA-RM-12-012: Support of coordinated analyses to define fundamental biological principles of exRNA generation, distribution, uptake, and effector function • RFA-RM-12-013, RFA-RM-12-014: Investigation of the possible clinical utility of exRNAs as biomarkers and therapeutic delivery vehicles RNAs can be exported from cells in extracellular vesicles, or bound to lipids or proteins, to circulate through the body and affect distant cells

  10. Extracellular RNA Communication Program Common elements shared by all exRNA RFAs: • Applications should involve multidisciplinary teams • Multi-PI leadership plans may be required • Web collaboration tool • Milestones-driven awards • Awardees from all 5 initiatives will form a consortium • Determine fundamental principles associated with exRNAs • Provide ready access of newly developed tools and resources to consortium members • Facilitate dissemination of data and technologies to the general research community • Data release/sharing • Applications from foreign institutions are acceptable • Note that RFA RM-12-010 can have a foreign component

  11. Extracellular RNA Communication Program Common elements shared by all exRNA RFAs: • Important dates: • Letter of Intent Due Date: October 12, 2012 • Application Receipt: November 13, 2012 • Scientific Merit Review: February – March 2013 • Advisory Council Review: May 2013 • Earliest Start Date: July 2013 • Kick-Off Meeting: September 26-27, 2013

  12. RFA RM-12-012 Extracellular RNA Biogenesis, Biodistribution, Uptake, and Effector Function (U19)

  13. RFA RM-12-012Extracellular RNA Biogenesis, Biodistribution, Uptake, and Effector Function (U19) Goals: • Encourage multidisciplinary teams of investigators to submit applications to determine the principles that guide the selection of regulatory RNA molecules for extracellular transport and to determine the function of these extracellular RNAs (exRNAs).  • The main scientific areas of interest include: (1) exRNA biogenesis, (2) biodistribution, (3) uptake of exRNA by target cells, and (4) the physiological impact of delivered exRNA in target cells/tissues.  • It is expected that enabling tools, technologies, bioreagents, and analytical approaches that elucidate pathways by which exRNAs are packaged, secreted, transported, and taken up by recipient cells will be developed.  Budget: • The U19 funding mechanism allows for multi-project applications. Total funds = 7.2 million total costs/yr to fund 4-6 projects.

  14. RFA RM-12-012 Select Review Criteria: • Are the exRNAs to be studied (if model systems are utilized) likely to be relevant to human biology? • How appropriate are the expertise and experience of the investigative teamin the context of exRNA? • ……do the project PD(s)/PI(s) have the necessary skills and experience to contribute to the success of this consortium?     • Will the complementary perspectives of the research team enable innovative approaches that would not be likely without a coordinated team effort? • Are the plans sufficiently flexible to exploit emerging research opportunities? • Are appropriate and quantifiable milestones and timelines clearly defined? • If the aims of the application are achieved, will the findings significantly increase our understanding of the biosynthetic pathways by which RNAs are directed for extracellular transport and of the mechanisms that regulate their secretion, biodistribution, uptake, and of their biological functions?

  15. RFA RM-12-011 Reference Profiles of Human Extracellular RNA (U01)

  16. RFA RM-12-011Reference Profiles of Human Extracellular RNA (U01) Goals: • Develop reference profiles for non-coding extracellular RNAs from healthy human blood and other body fluid samples.  • Generate a comprehensive catalog that is inclusive of exRNAs secreted in extracellular vesicles or bound to carriers. • Development of reference profiling methods that facilitate identification of both endogenously derived and exogenously obtained exRNA species. • Capture of trans-kingdom exRNAs such as those derived from diet or microbiome. • Development of tools, supporting methodologies and techniques. • Distinguishing endogenous and exogenously derived/trans-kingdom species. Budget: • 4.0 million total cost/year to fund 3-5 U01 applications.

  17. RFA RM-12-011 • RFA solely focused on human samples. • Projects should be based on existing samples. • Limited prospective collection for validation purposes. • Informed consents for use and sharing of sample and data should be in place. • A multidisciplinary team structure encouraged. • A fee for service type arrangement not responsive. • Animal or other non-human models not within scope.

  18. RFA RM-12-013 Clinical Utility of Extracellular RNA for Biomarker Development (UH2/UH3)

  19. RFA RM-12-013Clinical Utility of Extracellular RNA for Biomarker Development (UH2/UH3) • GOAL: To identify and quantify exRNA-based biomarkers derived from human body fluids • Utilizes UH2/UH3 Phased Cooperative Agreement mechanism • Applicants must submit a single application with the research strategy section divided into a 12-page UH2 exploratory phase and a 12-page UH3 phase for biomarker qualification and validation studies. • The maximum period of support for the combined UH2 and UH3 phases is 5 years. The UH2 phase can be for 1-2 years of support. The second UH3 phase can be for 3-4 years of support.

  20. RFA RM-12-013Clinical Utility of Extracellular RNA for Biomarker Development (UH2/UH3) • UH2 Exploratory phase should address the following: • plans to identify leads for potentially useful biomarkers; • plans to prioritize identified leads; • computer modeling or simulations and/or statistical justification for the number of subjects/samples proposed; clear scientific rationale for the range and types of subjects/samples to be used and involvement of key personnel with statistical expertise; • attention paid to variability in patient demographics, histology, prognosis, stage, and mode of detection; • matching of control subjects with case subjects; • outcome measures or primary data items for analysis reflecting sensitivity and specificity metrics; • sampling variability; • plans for confirmatory or cross validation studies with a new set of bio-specimens. • $500,000 total cost per year • Use of pre-existing biospecimen collection

  21. RFA RM-12-013Clinical Utility of Extracellular RNA for Biomarker Development (UH2/UH3) • UH3 biomarker validation/qualification phase may include the following: • Studies that correlates a biomarker with pathogenesis, disease processes, progression or regression of disease, response to therapy, accepted clinical endpoints, symptom management, etc • studies to design or improve the biomarker assay system to be robust, quantitative, reliable, and translatable to many laboratories, or to fall within costs that are appropriate for clinical use • studies to establish sampling or biomarker monitoring strategies that are non-invasive • studies to determine the relationship between biomarker measurements made from biofluids compared to those measurements obtained from tissues • studies to assess factors, such as sex, age, smoking behavior, etc., that are associated with biomarker status or level in control subjects • studies to assess factors associated with biomarker status or level in case subjects—in particular, disease characteristics such as stage, histology, grade, and prognosis • studies to assess the impact of covariates on the discriminatory abilities of the biomarker before clinical diagnosis, including demographics, disease-related characteristics, and other clinical information about the subject • $1,000,000 total cost per year • Prospective collection of biospecimens may be proposed in order to perform confirmatory or validation studies.

  22. RFA RM-12-014 Clinical Utility of Extracellular RNA for Therapy Development (UH2/UH3)

  23. RFA RM-12-014Clinical Utility of Extracellular RNA for Therapy Development (UH2/UH3) • GOAL: To develop and advance the therapeutic utility of exRNAs, RNA-containing extracellular vesicles (EVs) or exosomes, and/or exRNA-bound to other carrier molecules, such as lipoproteins and RNA-binding complexes. • Utilizes UH2/UH3 Phased Cooperative Agreement mechanism. • Applicants must submit a single application with the research strategy section divided into a 12-page UH2 phase consisting of proof of concept studies and another 12-page UH3 phase for the pre-clinical optimization, safety and toxicology studies. • The maximum period of support for the combined UH2 and UH3 phases is 5 years. The UH2 phase can be for 3 years of support. The second UH3 phase can be up to 3 years of support.

  24. RFA RM-12-014Clinical Utility of Extracellular RNA for Therapy Development (UH2/UH3) • UH2 proof of concept studies may include: • Feasibility studies in cell and animal models of disease • Targeting organ systems recalcitrant to therapeutic delivery • Crossing the blood-brain barrier and other physiological barriers • Delivering exRNA (miRNA, long non-coding RNA, mRNA, siRNA, etc.) to modulate gene expression and mitigate disease pathogenesis • Identification of surface markers for cell-specific targeting and fusion • Technologies for efficient loading of EVs and/or exRNA-binding complexes to serve as carriers for targeted delivery • Specific disruption of pathways in cases where intercellular-signaling mediated by exRNAs can lead to onset and progression of disease • Induction of immune response upon delivery of exRNA • $500,000 total cost per year

  25. RFA RM-12-014Clinical Utility of Extracellular RNA for Therapy Development (UH2/UH3) • UH3 phase may include: • preclinical efficacy testing; • predictive ADME (absorption, distribution, metabolism, and excretion) and toxicology testing; • optimization of candidate therapeutics; • formulation and stability studies, process development and manufacturing of candidate therapeutics; • development of SOPs and assays to support the production of cGMP materials for exRNA. This FOA supports only preclinical development, so production of clinical grade materials for clinical trial use is outside the scope; • pre-clinical pharmacology and toxicology studies. • $1,000,000 total cost per year

  26. RFA RM-12-010 Data Management and Resource Repository (DMRR) on Extracellular RNA

  27. RFA RM-12-010Data Management and Resource Repository (DMRR) on Extracellular RNA (U54) Goal: • Support a Data Management Resource/Repository (DMRR) for the ExRNA Program.  DMRR will integrate the efforts of all of the funded components of the program and serve as a community-wide resource for ExRNA standards, protocols, and data through the development of an ExRNA Atlas.  • Applications must be from US institution, but foreign components OK. Budget: • Set aside: $2.5M/year total costs maximum to fund 1 grant.

  28. DMRR U54 DMRR components/cores and activities include: Responsiveness: • Make sure your application has the three required components and the administrative core: 1. Scientific Outreach Component • ExRNA Atlas website (e.g. data, protocols ) • Support meetings, workshops, etc 2. Data Coordination Component • metadata standards • exRNA-seq data • other data types (e.g. genotype, phenotype) and data from outside program • Data deposition (e.g. GEO, dbGAP)

  29. DMRR U54 DMRR components/cores and activities include: 3. Data Integration and Analysis Component • Analysis tools and strategies (e.g. exogenous vs endogenous exRNAs) • exRNA catalogs • Software, tool, and “app” development • Help analyze data for integrative consortium papers • Help PIs funded by other RFAs analyze their data 4. Administrative Core • Facilitating interaction between three U54 components and rest of ExRNA consortium • ExRNA program teleconferences and workshops, steering committee meetings • Yearly consortium-wide meeting (50-100 attendees)

  30. DMRRReview Criteria Highlights • SIGNIFICANCE • INVESTIGATORS • ExRNA or RNA biology expertise? • RNA-seq data expertise?   • Experience managing a project of this magnitude? • INNOVATION • APPROACH • Are plans aligned with the anticipated DMRR activities? • Do plans support achievement of the proposed goals/milestones?  • Is the proposed DMRR data release plan appropriate for a community resource project?   • How well will the DMRR components integrate the efforts of all of the funded components of the ExRNA program and serve as a community-wide resource via an ExRNA Atlas?  • Data transportability and data interoperability in the future?  (Flexibility) • ENVIRONMENT • Letters of collaboration and institutional support show strong commitment to the project? 

  31. FAQ and Web Collaboration Tool • FAQs on the Extracellular RNA program http://commonfund.nih.gov/Exrna/faq.aspx • Web Collaboration Portal http://commonfund.nih.gov/Exrna/cwcp/index.aspx

  32. Questions for Working Group? Working Group Members • Alexandra Ainsztein, Ph.D., Program Director, National Institute of General Medical Sciences (NIGMS) • Maureen Beanan, Ph.D., Program Director, National Institute of Allergy and Infectious Diseases (NIAID) • Philip J. Brooks, Ph.D., Program Director, National Center for Advancing Translational Sciences (NCATS) • Michelle Freund, Ph.D., Program Director, National Institute of Mental Health (NIMH) • Christine Gatlin, Ph.D., Program Director, National Human Genome Research Institute (NHGRI) • Max Guo, Ph.D., Chief, Genetics and Cell Biology Branch , National Institute on Aging (NIA) • George A. McKie, D.V.M., Ph.D., Program Director, National Eye Institute (NEI) • Matthew Reilly, Ph.D. , Program Director, Genetics & Proteomics , National Institute on Alcohol Abuse and Alcoholism (NIAAA) • John Satterlee, Ph.D., Program Director, National Institute on Drug Abuse (NIDA) • Pothur R. Srinivas, Ph.D., M.P.H., Program Director, National Heart, Lung, and Blood Institute (NHLBI) • Robert Star, M.D., Director, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) • Xenia Tigno, Ph.D., M.S., Program Director, National Institute of Nursing Research (NINR) • SundarVenkatachalam, Ph.D., Program Director, National Institute of Dental and Craniofacial Research (NIDCR) • Steven Zullo, Ph.D., Program Director, National Institute of Biomedical Imaging and Bioengineering (NIBIB) Working Group Coordinators: • T. Kevin Howcroft, Ph.D., Program Director , National Cancer Institute (NCI) • Suresh Mohla, Ph.D. , Chief (TBMB) and Division Associate Director , National Cancer Institute (NCI) • Danilo A. Tagle, Ph.D., Associate Director for Special Initiatives, National Center for Advancing Translational Sciences (NCATS) Scientific Review Officer: • Richard Panniers, Ph.D., Chief , Center for Scientific Review (CSR) Grants Management Specialists: • Cheryl Nathaniel, National Institute on Drug Abuse (NIDA) • Tracee S. Gilchrist, National Heart Lung and Blood Institute (NHLBI) • Crystal Wolfrey, National Cancer Institute (NCI) • Christina Fleming, National Center for Advancing Translational Sciences (NCATS) • Judy Musgrave, National Center for Advancing Translational Sciences (NCATS) NIH Common Fund • Patricia (Trish) Labosky, Ph.D., Program Leader, National Institutes of Health (NIH)

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