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

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

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

• 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

• 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

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

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

• 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

• 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

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.

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

Integrative Physiology and Genetics of Bone

• FGF23– From osteocytes

– Phosphate homeostasis

• Osteocalcin – From osteoblasts

– Glucose metabolism

• Sclerostin– From osteocytes

– Bone formation

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KIDNEY

OSTEOBLAST

OSTEOCYTE

PANCREAS

Three Recent Developments

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• 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

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

• 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 DiseasePreclinical Translational Research