The role of maternal obesity in osteoarthritis

项目摘要 在这份K 01提案中，Arin Oestreich博士提出了一份详细的职业发展计划，最终将在 一个独立的学术职位Oestreich博士将获得以下方面的关键技能：（1） 骨关节炎（OA），（2）使用单核测序的染色质分析和转录组学分析，和（3） 生物信息学方法整合多组学平台和破译信号通路编程 母亲肥胖Oestreich博士独特地将她在孕产妇肥胖方面的背景与OA方面的新培训相结合 来提升她的科学事业凭借这种独特的双重专业知识和初步数据，Oestreich博士 将有能力开发一个独立的研究计划，重点研究特定的 母亲肥胖环境的组成部分对后代关节健康的影响。 该项目的科学目标是确定母体n-6 HFD对表观遗传调控的影响， 控制后代OA风险的机制，并分离母体膳食n-6脂肪酸对 编程后代OA。目的1将检验母体富含n-6的HFD会增加 损伤诱导的OA在成年后代，并确定发育暴露的关键窗口。目的2 将检验母体n-6 HFD通过稳定改变表观遗传基因直接编程膝关节的假设。 肌肉骨骼祖细胞在发育过程中的景观。这一目标将使用多体单核 表观基因组和转录组的测序以追求遗传靶点， 母亲肥胖，并且已知会增加成人膝关节骨性关节炎的严重程度。目标3将检验以下假设： 控制肥胖母鼠的n-6：n-3脂肪酸比例将减少母胎炎症， 成年后代发展OA。通过确定特定母体膳食脂肪酸对胎儿的影响， 肢体发育，本提案中收集的数据对于制定产前维生素将是非常宝贵的， 最佳比例的n-3 PUFA作为一种新的策略，以保护成年后代关节健康。 在K 01的支持和职业发展计划中提供的培训下，Oestreich博士将 独特的准备实现她的主要目标，成为一个独立的研究人员在发展领域的 肌肉骨骼疾病的规划。

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.