R01AR078559

Mechanisms That Couple Irregular Development of Fetal Melanoblasts to Premature Exhaustion of Adult Melanocyte Stem Cells - Project Summary

Maintenance of tissue function during adulthood, and hence suppression of tissue degeneration and disease, depends on maintenance of stem cell populations. Adult stem cells are epigenetically programmed and a culmination of a series of developmental decisions initiated in the embryo.

In utero environmental exposures on the embryo can influence adult and late-life disease, likely in part via effects on stem cell development that are transmitted to maintenance and function of stem cells in the adult. However, the molecular links between embryonic development and long-term maintenance of stem cell function and phenotype in adults are poorly defined.

We will employ lineage-specific genetic inactivation of a histone chaperone to understand how embryonic developmental integrity of melanoblasts (MB) impacts on maintenance adult melanocyte (MC) stem cells (MCSC). The histone chaperone HIRA deposits histone variant H3.3 into active genes, promoters, and enhancers.

Through in vitro and in vivo studies and single-cell RNA-Seq of mouse embryo melanoblasts (MBs) from wild-type mice and mice lacking expression of HIRA in embryonic MBs, we have uncovered a role for HIRA in sustaining the PAX3/SOX10-MITF MB specification pathway. Inactivation of HIRA in MBs depletes the number of MBs in early/mid-stage embryos. However, this embryonic defect is rescued by birth, and young mice exhibit normal numbers of melanocytic cells, and only a very subtle pigmentation defect.

Nevertheless, in newborn mice, HIRA knockout (KO) melanocytic cells exhibit a higher frequency of telomere-associated DNA damage foci, indicating that HIRA KO MCSC and/or melanocytes harbor molecular damage, even in newborn mice. Indeed, melanoblasts and melanocytes from newborn HIRA KO mice respond poorly to pro-proliferative challenge in vitro and in vivo, and these mice show marked accelerated MCSC and melanocyte depletion and dramatically accelerated hair greying during adulthood.

Building on these extensive preliminary data, we will investigate the role of HIRA in differentiation and development of the melanocytic lineage and investigate the links between abnormal embryonic development and adult stem cell depletion during adulthood and aging. Dysregulation of the PAX3/SOX10-MITF signaling pathway contributes to developmental disorders and melanoma. These studies to define HIRA's role in the PAX3/SOX10-MITF axis can promote therapeutic interventions to combat these developmental and neoplastic disorders. Moreover, completion of these specific aims will address how the integrity of embryonic development of tissue-specific stem cells impacts maintenance of those stem cells during adulthood.

Sanford Burnham Prebys Medical Discovery Institute

THE NATIONAL INSTITUTE OF AND MUSCULOSKELETAL AND SKIN DISEASES (NIAMS) MISSION IS TO SUPPORT RESEARCH INTO THE CAUSES, TREATMENT, AND PREVENTION OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES, TRAINING OF BASIC AND CLINICAL SCIENTISTS TO CARRY OUT THIS RESEARCH, AND DISSEMINATION OF INFORMATION ON RESEARCH PROGRESS IN THESE DISEASES. THE EXTRAMURAL PROGRAM PROMOTES AND SUPPORTS BASIC, TRANSLATIONAL, AND CLINICAL STUDIES OF SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES, SKIN BIOLOGY AND DISEASES, BONE BIOLOGY AND DISEASES, MUSCLE BIOLOGY AND DISEASES, AND JOINT BIOLOGY AND DISEASES AND ORTHOPAEDICS. NIAMS SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES PROGRAMS ADDRESS BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH, INCLUDING CLINICAL TRIALS AND OBSERVATIONAL AND MECHANISTIC STUDIES, FOCUSED ON IMMUNE-MEDIATED ARTHRITIS AND AUTOIMMUNE-RELATED ACUTE AND CHRONIC DISORDERS IN ADULTS AND CHILDREN. NIAMS SKIN BIOLOGY AND DISEASES PROGRAMS SUPPORT BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH IN SKIN, INCLUDING BOTH COMMON AND RARE SKIN DISEASES. THESE PROGRAMS INCLUDE INVESTIGATIONS OF THE BASIC MOLECULAR, CELLULAR, AND DEVELOPMENTAL BIOLOGY OF SKIN, AS WELL AS STUDIES OF SKIN AS AN IMMUNE, SENSORY, ENDOCRINE, AND METABOLIC ORGAN. NIAMS BONE BIOLOGY AND DISEASES PROGRAMS SUPPORT RESEARCH ON THE CONTROL OF BONE FORMATION, RESORPTION, AND MINERALIZATION AS WELL AS THE EFFECTS OF SIGNALING MOLECULES ON BONE CELLS. THEY SUPPORT CLINICAL STUDIES OF INTERVENTIONS TO PREVENT FRACTURES ASSOCIATED WITH OSTEOPOROSIS AND RESEARCH INTO LESS COMMON BONE DISEASES. NIAMS MUSCLE BIOLOGY AND DISEASES PROGRAMS ENCOURAGE RESEARCH ON MUSCLE DEVELOPMENTAL BIOLOGY, GROWTH, MAINTENANCE, AND HYPERTROPHY, PHYSIOLOGY OF CONTRACTION, STRUCTURAL BIOLOGY OF THE CONTRACTILE APPARATUS, DISEASE MECHANISMS, BIOMARKERS AND OUTCOME MEASURES, AND DEVELOPMENT AND CLINICAL TESTING OF THERAPIES FOR CONDITIONS INCLUDING THE MUSCULAR DYSTROPHIES. NIAMS JOINT BIOLOGY, DISEASES, AND ORTHOPAEDICS PROGRAMS SUPPORT A BROAD SPECTRUM OF RESEARCH CENTERED ON THE INTERPLAY AMONG THE BODY'S MUSCLES, BONES, AND CONNECTIVE TISSUES. THEY ENCOURAGE TISSUE ENGINEERING AND REGENERATIVE MEDICINE RESEARCH, MOLECULAR BIOLOGY, IMAGING, AND CLINICAL RESEARCH, AND THE TREATMENT AND PREVENTION OF ORTHOPAEDIC CONDITIONS. NIAMS PARTICIPATES IN THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS. THE SBIR PROGRAM IS INTENDED 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. THE STTR PROGRAM IS INTENDED TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND 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.

93.846 - Arthritis, Musculoskeletal and Skin Diseases Research

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [HHS - NIH]

La Jolla, California 920371005 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 417% from $600,533 to $3,102,648.