P01AG071463

Multicomponent Therapy for Age-Related Skin Stem Cell Deficiency - Summary

Chronic ulcers, defined as wounds that fail to heal within a three-month period, are associated with age-related dysfunction in skin stem cells. This dysfunction not only blunts tissue repair but also contributes to skin fragility, atrophy, and the "aging phenotype" that has clinical and psychosocial implications. Non-healing ulcers in aging individuals represent a multibillion-dollar burden in the United States and globally, both in terms of healthcare resources and reduced productivity.

However, it is recognized that the basic biology and the influence of age-associated changes on wound healing are poorly understood, and there are numerous research questions still to be answered. To address this important issue, we have assembled a highly collaborative and multidisciplinary team of investigators with established track records in skin pathology, regenerative and stem cell biology, wound healing, bioinformatics, and the pathobiology of aging.

We have also leveraged the resources of seven Harvard institutions to develop a unified and state-of-the-art approach to decipher the role of skin stem cell deficiency in age-related defective wound healing. Additionally, we have generated data-based hypotheses and identified inter-project synergies that will maximize productivity and translational focus.

Our fundamental hypothesis is that the identification and interrogation of three major, inter-related, and therapeutically targetable/reprogrammable pathways relevant to age-related skin stem cell dysfunction - metabolic, epigenetic, and membrane transporter/receptor pathways - will pave the way for combinatorial (multicomponent) therapies necessary for more robust healing and regenerative responses to skin injury.

To pursue this goal, we have developed six strategies:
1) Discovery of biomarkers for epidermal and dermal stem cell identification and manipulation.
2) Determination of metabolic regulators required for epidermal progenitor activity and maintenance.
3) Identification of novel epigenetic pathways that govern skin stem cell function and vitality.
4) Development and evaluation of unique murine models that permit the study of human wound healing in vivo.
5) Deployment of lineage tracking technologies that facilitate the detection of experimentally-manipulated stem cell fate in healing wounds.
6) Generation of new animal strains for epigenomic induction of premature aging and methods for genomic restoration of stem cell youth and pluripotency.

Our overall aims seek to answer the following questions:
1) How can one map the key metabolomic, epigenetic, and cell receptor stem cell pathways that drive age-related wound healing dysfunction?
2) What are the therapeutically accessible nodes for stem cell-directed multicomponent combinatorial targeting within these pathways?
3) What are the agents that are likely to affect the restoration of robust and regenerative stem cell-driven responses to wound healing and support physiologic cutaneous maintenance and health?

Success in this endeavor could be transformative in understanding how aged stem cells may be restored to functional vigor, implicit to normal tissue integrity and regenerative potential.

Brigham & Womens Hospital

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Boston, Massachusetts 021156110 United States

Single Zip Code

NIA Program Project Applications (P01 Clinical Trial Optional) (PAR-19-314)

Amendment Since initial award the total obligations have increased 296% from $2,273,417 to $9,002,424.