The role of maternal obesity in osteoarthritis

母亲肥胖在骨关节炎中的作用

基本信息

批准号：
10602435
负责人：
Arin Kettle Oestreich
金额：
$ 12.81万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-05 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10602435
关键词：
Acceleration Adult Adult Children Affect Animal Model Behavior Bioinformatics Biological Assay Breeding Candidate Disease Gene Cell Nucleus Cells Chromatin Coupled DNMT3B gene Data Degenerative polyarthritis Development Development Plans Diagnosis Diet Dietary Component Dietary Fatty Acid Dietary Intervention Disease Doctor of Philosophy Embryo Epigenetic Process FAT gene Faculty Fatty Acids Fatty acid glycerol esters Fetal Growth Flow Cytometry Generations Genes Genetic Goals Growth Health High Fat Diet High Prevalence Histologic Hypertension Inflammation Inflammatory Injury Insulin Joints Knee Knee joint Life Limb Development Longevity Macrophage Measures Medial meniscus structure Metabolic Molecular Morphology Mus Musculoskeletal Musculoskeletal Development Musculoskeletal Diseases Musculoskeletal System Nucleic Acid Regulatory Sequences Obesity Omega-3 Fatty Acids Omega-6 Fatty Acids Operative Surgical Procedures Outcome Overnutrition Pain Pharmaceutical Preparations Population Positioning Attribute Predisposition Pregnancy Prenatal Nutrition Regulation Reproduction Research Research Personnel Risk Role Secondary to Serum Severities Signal Pathway Signal Transduction Synovitis Testing Training Transgenic Mice Transgenic Organisms Transposase Vitamins Work bisulfite sequencing candidate validation career career development cartilage degradation cartilage development chromatin immunoprecipitation cytokine design dietary effectiveness evaluation epigenome fetal implantation improved in utero joint formation joint injury maternal obesity microCT mother nutrition multiple omics non-alcoholic fatty liver disease novel novel strategies obese person obesity in pregnancy obesogenic offspring pregnancy health prenatal progenitor programs single nucleus RNA-sequencing skills stem cells subchondral bone transcriptome transcriptomics translational approach western diet

项目摘要

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.

项目概要在这份 K01 提案中，Arin Oestreich 博士提出了详细的职业发展计划，最终将独立的学术教职职位。 Oestreich 博士将获得 (1) 动物模型的关键技能骨关节炎 (OA)，(2) 使用单核测序进行染色质分析和转录组分析，以及 (3) 整合多组学平台并破译信号通路的生物信息学方法产妇肥胖。 Oestreich 博士独特地将她在孕产妇肥胖方面的背景与 OA 的新培训结合起来以加强她的科学事业。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，重点研究特定的影响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。目标 1 将检验母体 n-6 丰富的 HFD 会增加严重程度的假设成年后代中损伤诱发的 OA 并确定发育暴露的关键窗口。目标2 将检验母亲 n-6 HFD 通过稳定改变表观遗传直接编程膝关节的假设发育过程中肌肉骨骼祖细胞的景观。该目标将使用多组学单核表观基因组和转录组测序以追求遗传目标受到表观遗传调控已知母亲肥胖会加剧成人膝关节骨关节炎的严重程度。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并保护胎儿患有 OA 的成年后代。通过确定特定母亲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具有无价的价值 n-3 PUFA 的最佳比例作为保护成年后代关节健康的新策略。借助本次K01的支持以及她职业发展计划中提供的培训，Oestreich博士将独特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。