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keywords
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aging
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keywords
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senescence
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overview
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My lab focuses on aging, in particular in relationship to stem cells and tissue function. This includes age-associated bone homeostasis, autophagy and senescence. One of the primary areas of research is age-associated changes in the epigenetic regulation of stem cells, in particular miRNAS and Hdacs. We also study the role of the cytokine CXCL12 and its proteolytic metabolites that have separate cryptic biological activity. This not only has an impact on bone biology with aging, but has implications in many other areas, such as immunology and cancer biology. We are also interested in aging effects of the Kynurenine pathway on different organ systems including musculoskeletal and CNS. Our lab has a strong clinical translational and tech transfer focus. We have a patent portfolio and have spun off a start-up drug delivery company, SpheroFill, LLC.
Over the last several years we have focused on the exciting developing role of the tryptophan metabolite Kynurenine (KYN) and it’s signaling through the aryl hydrocarbon receptor (AhR) pathway in aging and disease. We have demonstrated its importance in inhibiting bone formation with age, as well as increasing osteoclast driven bone resorption. Most recently and relevant to the current Merit Award proposal we have identified that it drives BMSC senescence while simultaneously blocking autophagy. Senescence has emerged as a critical process in osteoporosis and age-related bone loss. With our collaborators we have been developing inducible conditional KO mouse models centered on AhR, IDO-1 and now KYN pathway enzymes. We have also identified age-associated miRNA changes in directly isolated (non-cultured) human bone marrow Mesenchymal Stem Cells (BMSCs). Further, we have started to look in detail at several of these miRNAs and their effect on BMSC osteogenic potential (U.S. Patent No. 9,267,139 [see MyBibliography]). Critically we have identified overlapping miRNAs whose expression is altered by KYN and targets osteogenesis. One of these miR-29b-1-5p is among a set of “passenger” strand miRNAs that are normally degraded, but with aging have become the dominant miRNA strand via an arm-switching process tied into kynurenine signaling through the Aryl Hydrocarbon Receptor. These miRNAs target osteogenic cytokines, including SDF-1 (aka: CXCL12), multiple signaling pathways, transcription factors and extracellular matrix molecules. We have also seen that they change with age in the same manner in murine BMSCs, muscle and bone, and that their expression can be altered via nutrient signaling pathways including diets with modified aromatic amino acids, caloric restriction or leptin treatment. The role of the SDF-1/CXCR4/ACKR3 axis, and related miRNAs, on osteogenesis in aging is a major focus of my lab. With our P01 collaborators we have identified increased kynurenine levels with age as a unifying pathway that links epigenetic changes in SDF-1 targeting miRNAs, histone deacetylases, decreased SDF-1, increased BMSC lipogenesis and decreased osteogenesis with age-related bone loss. Importantly we have demonstrated that the proteolytic processing of SDF-1 generates novel bioactive metabolites. Additionally, I have experience with aging effects on in vitro and in vivo tissue repair and on epigenetic regulation of skeletal stem cells, as well as cell death and survival pathways. This has included the first demonstration of SDF-1 mediated regulation of autophagy and has resulted in a second patent application (U.S.S.N. 61/712/708). I am interested in clinical translational development of our basic science research and have started a biotech company (SpheroFill, LLC) focused on a novel porous walled hollow glass microsphere drug delivery platform for which we received US Patent No. 10,201,633 Issued 2-12-2019 and an NSF STTR award 2112233.
Recently we have received funding to take the work we have performed determining the role of the Kynurenine Pathway and related signaling and enzyme pathways in driving senescence and bone loss in aging and to see if this is also driving CNS brain aging and Alzheimer’s disease development. The Kynurenine Pathway is now considered to be a critical factor in general aging and longevity. Together with my collaborators Dr. Gavin Wang and Dr. Carsten Krieg we will be starting this project utilizing cutting edge technologies including CITE-seq and CyTOF to look at single cell level protein and gene expression changes as well as Spatial Transcriptomics to see the tissue level distribution of changes.
Other Aging collaborations: In addition to the Aging Musculoskeletal P01 research group based out of Augusta University, that I have been part of for over 15 years, I have been helping to develop an MUSC Musculoskeletal Research group focused on aging. My lab has been working with the MUSC Dept of Orthopaedics & Physical Medicine collecting human bone marrow samples to isolate different stem cell populations to identify changes in genes and their regulation at different ages and from different genders, and I have been working with Amanda LaRue, Ph.D. (ACOS-Research, Ralph H. Johnson VAMC & Dept of Pathology Vice Chair for Research) since the early 2000’s on bone marrow stem cell isolation, transplantation and function especially in the context of aging and changes in epigenetic regulation with aging. I am also exploring with Chad Novince (MUSC Dental College) the potential role of the microbiome in the regulation of bone homeostasis, as well as other systems, with age. Uniquely my lab is identifying how post-translational changes to SDF-1 with age has implications with and beyond bone homeostasis - including cardiovascular, immune system regulation and cancer biology. I am currently working with MUSC endocrinologists and GPCR researchers such as Joe Blumer (MUSC) and Brian Volkman (MCW) to understand these CXCL12 modifications and how they alter known signaling systems and generate novel cryptic ligands that target previously unrecognized signaling pathways leading to senescence and dysfunctional bone homeostasis.
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