The role of maternal obesity in osteoarthritis

项目总结 在这份K01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 一个独立的学术教员职位。Oestreich博士将在(1)动物模型中获得关键技能 骨关节炎(OA)，(2)染色质图谱和单核测序转录分析，以及(3) 生物信息学方法整合多组平台并破译由编程的信号通路 母体肥胖。Oestreich博士独特地将她在母亲肥胖方面的背景与在OA方面的新培训结合在一起 来提升她的科学事业。配备了这种独特的双重专业知识和初步数据，Oestreich博士 将处于有利地位，以制定一个独立的研究计划，重点研究特定的影响 母亲肥胖环境的组成部分对子代联合健康的影响。 该项目的科学目标是确定母体n-6hfd对表观遗传调节的影响。 控制子代骨性关节炎风险的机制以及分离母亲饮食中n-6脂肪酸对 为后代的办公自动化编程。目的1将验证母亲n-6富集型HFD增加严重程度的假设 并确定发育过程中暴露的关键窗口。目标2 将检验这一假设，即母亲的n-6HFD通过稳定地改变表观遗传学来直接对膝关节进行编程 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目标是受表观遗传调控的 母体肥胖会加重成人膝关节骨性关节炎的严重程度。目标3将检验这一假设 控制肥胖大鼠的n-6：n-3脂肪酸比例将减少母婴炎症，保护 发育成骨性关节炎的成年后代。通过测定特定母体膳食脂肪酸对胎儿的影响 关于肢体发育，这项提案中收集的数据将对制定产前维生素和 N-3多不饱和脂肪酸的最佳比例作为保护成年后代关节健康的新策略。 在这位K01的支持和她的职业发展计划中提供的培训下，Oestreich博士将成为 独一无二地准备实现她的主要目标--成为发展领域的独立研究员 肌肉骨骼疾病的编程。

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.