The role of maternal obesity in osteoarthritis

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PROJECT SUMMARY In this K01 proposal, Dr. Arin Oestreich, PhD, presents a detailed career development plan that will culminate in an independent academic faculty position. Dr. Oestreich will obtain critical skills in (1) animal models of osteoarthritis (OA), (2) chromatin profiling and transcriptomic analysis using single nucleus sequencing, and (3) bioinformatic approaches to integrate multiomic platforms and decipher signaling pathways programed by maternal obesity. Dr. Oestreich uniquely combines her background in maternal obesity with new training in OA to enhance her scientific career. Equipped with this unique dual expertise and preliminary data, Dr. Oestreich will be well positioned to develop an independent research program focused on studying the effects of specific components of the maternal obese milieu on offspring joint health. The scientific goal of this project is to determine the impact of maternal n-6 HFD on the epigenetic regulatory mechanisms governing offspring OA risk and to isolate the effect of maternal dietary n-6 fatty acids on programming offspring OA. Aim 1 will test the hypothesis that maternal n-6 enriched HFD increases the severity of injury-induced OA in the adult offspring and determine the critical window of developmental exposure. Aim 2 will test the hypothesis that maternal n-6 HFD directly programs the knee joint by stably altering the epigenetic landscape of the musculoskeletal progenitors during development. This aim will use multiomic single nucleus sequencing of the epigenome and transcriptome to pursue genetic targets are epigenetically regulated by maternal obesity and known to heighten OA severity in the adult knee. Aim 3 will test the hypothesis that controlling the n-6:n-3 fatty acid ratio in obese dams will decrease maternal-fetal inflammation and protect the adult offspring from developing OA. By determining the impact of specific maternal dietary fatty acids on fetal limb development, the data collected in this proposal will be invaluable for formulating prenatal vitamins with optimal ratios of n-3 PUFAs as a novel strategy to protect the adult offspring joint health. With the support of this K01 and the training provided in her career development plan, Dr. Oestreich will be uniquely poised to attain her primary goal of becoming an independent researcher in the field of developmental programming of musculoskeletal disease.