2011 NIAMS Extramural Scientific Planning Retreat

1. 2011 NIAMS Extramural Scientific Planning Retreat Goals: • Review ongoing and emerging areas of science • Identify needs, gaps, and opportunities that would not be pursued otherwise • Review funding mechanisms or activities to develop policies to adapt to the current science and funding environment • To introduce new tools and approaches to conduct scientific portfolio analysis

2. Portfolio Analysis Goals Portfolio analysis tools were used to: • Assess outcome indicators of supported research • Evaluate methods for identifying science trends and contributions of funded research • Improve our understanding of on-going studies and emerging areas of research

3. Retreat Topics • Common Pathways Leading to High Impact Discoveries • Skin Innate Immunity • Scleroderma Research • Developments in Musculoskeletal Tissue Engineering and Regenerative Medicine • Muscle Disease Preclinical Translational • Research Developments and Trends in Integrative Physiology and Genetics of Bone

4. Common Pathways Leading to High Impact Discoveries • Retrospective analyses suggest key research discoveries follow a common path • From conception to application (e.g., testing a new therapy in a clinical trial) may require a substantial amount of fundamental research • Basic research activity may peak decades prior to actual use • “Vital signs” predict future innovation in a field • Number of publications • Integration of publications into a sizeable knowledge pool • Convergence of information from other knowledge fields • Often required to move from a clear research goal to a product

5. Common Pathways Leading to High Impact Discoveries • Predictors of project potential • Number of projects • Overlap among projects • Sequence of initiating new projects and evaluating results from ongoing research • Funding the discovery process • Seed funding from non-NIH sources provides rapid support for high-risk/high-reward research • Targeted NIH support fills important gaps • Interdisciplinary meetings with scientists and advocates to advance research • Portfolio analysis may help these efforts, by identifying critical gaps and needs

6. Skin Innate Immunity • What are the most important discoveries in the field and what has been the NIAMS contribution? (Projects and publications that fostered turning points in research topics) • Stat3 activation of keratinocytes in a psoriasis mouse model • Commensal bacteria regulation of Toll-like receptor 3-dependent inflammation after skin injury • Identification of tyrosinase variants and autoimmunity susceptibility in a vitiligo genome-wide association study • Influential publications can increase the number of grant applications in a topic, e.g., anti-microbial peptides (AMPs) • Importance of AMP-induced syndecan in wound healing • Microbial upregulation of AMP production and inflammation • High AMP levels in psoriasis and low AMP levels in atopic dermatitis

7. Skin Innate Immunity • Emerging trends, reflected in new focus areas among current pending applications • Methicillin-resistant Staphylococcus aureus (MRSA) • Mast cell biology • Role of the inflammasome in skin diseases • Functional genetic studies of immune-mediated skin diseases • Areas for further study: gaps and opportunities • Signal transduction pathways • Interactions between host factors and the skin microbiome • Role of the innate immune system on wound healing • Therapeutic development, targeting the innate immune system and/or based on anti-microbial peptides

8. Scleroderma Research • NIH funding, FY 2001-2010 • NIAMS funding was fairly flat • Non-NIAMS NIH funding increased • 33 ongoing NIAMS-funded projects • In four programs in the Division of Skin and Rheumatic Diseases • Examples of key NIAMS-supported scleroderma research advances • Mechanisms of fibrosis • Factors that contribute to vascular abnormalities • Role of innate and adaptive immune systems • Genome-wide Association Studies

9. Scleroderma Research • NIAMS-supported clinical research advances • Improved quality of life with cyclophosphamide treatment • Development of new biomarkers and clinical outcome measures • Growing interest from pharmaceutical industry • Less competition in scleroderma field • New therapeutic targets • Transforming growth factor β (TGFβ) pathway • Caveolin-1 • Cytokine inhibitors (interleukin-1, -6, and -13) • Environmental triggers of inflammation through the innate immune system

10. Musculoskeletal Tissue Engineering and Regenerative Medicine (TE/RM) Selected Themes • Opportunities exist in osteoarthritis for TE/RM approaches • Senior investigators have developed promising approaches – stem cells, scaffolds, and growth factors – for early osteoarthritis prevention and potential bio-implants for future use. • Complex tissues are attracting young investigators • Several new investigators have focused their work at the interface of musculoskeletal tissues (e.g., ligament/bone), which is particularly challenging because of the added complexity of projects involving multiple tissues. • Promising commercialization opportunities • Some small businesses have already found success at various commercial stages, indicating a strong desire by the private sector to invest in TE/RM research and products. • Collaboration with other federal agencies has been fruitful • For example, the Armed Forces Institute of Regenerative Medicine (AFIRM) is currently the largest federal endeavor in TE/RM. NIH and NIAMS have played a critical role. • Mesenchymal stem cells (MSC) have shaped the field • Following the initial groundbreaking discoveries, the number of publications and applications has grown rapidly over the last decade.

11. Musculoskeletal Tissue Engineering and Regenerative Medicine • Challenges and Opportunities • Understanding and controlling the cellular response • Formulating biomaterials scaffolds and the tissue matrix environment • Promoting translation and commercialization • Building and training multidisciplinary research teams, e.g., integrating developmental biology with TE/RM and getting clinicians involved • Developing imaging tools and model systems (virtual/mathematical models and in vitro assays predicting in vivo performance) • in vivo testing in large animal models; and engineering/maintaining complex and functional tissues • Lessons Learned • Setting realistic expectations and obtainable goals in order to maintain scientific momentum and public support • Basic research remains paramount. Includes mechanisms of tissue development and cell behavior

12. Integrative Physiology and Genetics of Bone • FGF23 • From osteocytes • Phosphate homeostasis • Osteocalcin • From osteoblasts • Glucose metabolism • Sclerostin • From osteocytes • Bone formation 1 Three Recent Developments PANCREAS 2 2 OSTEOBLAST 3 3 1 OSTEOCYTE KIDNEY

13. Integrative Physiology and Genetics of Bone • Advances and funding • FGF23 and phosphate homeostasis • Considerable NIH support, including an FY 2004 solicitation for studies of the mechanisms of mineralization in bone (RFA-AR-04-001) • Osteocalcin and glucose metabolism • Serendipitous discovery leveraging NIH support • Osteocytes and bone formation • Initial support from industry and other non-NIH sources • Implications for future investments • Accommodate the long timeline of scientific progress • Stable, diverse scientific environment • Nurture unexpected, high-risk/high-reward discoveries • Agile funding process

14. Muscle DiseasePreclinical Translational Research • Potential therapeutic strategies • Replace the mutated gene • Gene therapy • Cell Therapy • Repair gene products • Exon skipping • Stop codon RT • Substitute a functional protein • Utrophin therapies • Integrin therapies • Results • Most are safe and efficacious in animals • Few have been tested in humans • Treat downstream sequelae • Membrane repair • Edema and apoptosis • Muscle anabolics • Fibrosis inhibitors

15. Muscle DiseasePreclinical Translational Research • Recognize new paradigm • From single focus to multi-disciplinary studies • From individual experiments to high-throughput strategies • From hypothesis testing to milestone-driven accomplishments • Encourage public-private partnerships • Engage experienced translational researchers in peer review • Incorporate a long-term therapy development plan into the review criteria • Guide investigators • Cooperative agreement mechanisms • Encourage applicants to work closely with NIH staff as they develop their projects