1. 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 2011 NIAMS Extramural Scientific Planning Retreat

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. 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 Common Pathways Leading to High Impact Discoveries

5. 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 Common Pathways Leading to High Impact Discoveries

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. 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 Scleroderma Research

9. 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 Scleroderma Research

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 1 2 2 3 3 KIDNEY OSTEOBLAST OSTEOCYTE PANCREAS Three Recent Developments 3 3 2 2 1 1

13. 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 Integrative Physiology and Genetics of Bone

14. Muscle Disease Preclinical 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. 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 Muscle Disease Preclinical Translational Research