Menopausal Knee-ds: Elucidating mechanisms and treatments for knee osteoarthritis

更年期膝关节：阐明膝骨关节炎的机制和治疗方法

• 批准号: 10749297
• 负责人: Gabrielle Gilmer
• 金额: $ 5.27万
• 依托单位: SPAULDING REHABILITATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749297
• 关键词: 4-vinylcyclohexene diepoxide; Address; Adult; Affect; Age; Aging; Animal Model; Animals; Attenuated; Biological; Cardiovascular Diseases; Cartilage; Chemicals; Chondrocytes; Complex; Coupling; Degenerative polyarthritis; Disease; Doctor of Philosophy; Dose; Drops; Elements; Engineering; Environment; Estradiol; Exposure to; Feedback; Fellowship; Female; Flow Cytometry; Genes; Genetic; Goals; Health; Histopathology; Hormone use; Human; Image; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Incidence; Institution; International; Intervention; Knee; Knee Osteoarthritis; Literature; Mediating; Menopause; Mentors; Meta-Analysis; Modality; Modeling; Molecular; Mus; Mutation; Orthopedic Surgery; Ovarian Follicle; Pathologic; Pathology; Pathway interactions; Performance; Perimenopause; Persons; Phenotype; Physicians; Physiological; Physiology; Postmenopause; Premature Menopause; Process; Proteins; Proteolysis; Regulation; Rehabilitation therapy; Rejuvenation; Repression; Research; Rodent; Role; Scientist; Severities; Sex Differences; Signal Transduction; Societies; Students; System; Techniques; Testing; Therapeutic; Thromboembolism; Time; Tissue Engineering; Tissues; Training; Transfection; Ubiquitin; Ubiquitin-mediated Proteolysis Pathway; Ubiquitination; Universities; Woman; Work; adverse event risk; age related; alternative treatment; arthropathies; biological systems; cartilage degradation; design; effective therapy; gene therapy; genome wide association study; hormone therapy; improved; in vivo; insight; interest; joint injury; live cell imaging; male; medical schools; men; middle age; multicatalytic endopeptidase complex; multidisciplinary; promoter; protein degradation; response; synthetic biology; therapy outcome; tool; ubiquitin-protein ligase

PROJECT SUMMARY/ABSTRACT Background: As of 2020, an estimated 654.1 million adults live with knee osteoarthritis (KOA), and women who are post-menopausal are nearly twice as likely to develop KOA compared to men. Despite this, most animal studies on KOA include only males, and, of the few studies utilizing females, menopause is typically not included, as it is not a naturally occurring process in non-primates. As such, there is a paucity of literature aimed at understanding mechanisms of menopause associated KOA and a corresponding absence of treatment interventions specifically for post-menopausal people with KOA. As a part of my PhD work thus far, I have developed a chemically-induced menopause model by injecting middle-aged female mice with 4- vinylcyclohexene diepoxide (VCD). I have confirmed this model displays a menopausal phenotype, including perimenopause, and that these mice display more severe KOA than age-matched, non-menopausal mice. The research goals of this fellowship are to interrogate mechanisms of menopause-induced KOA using our VCD model (Specific Aim 1) and employ synthetic biology techniques to lay the groundwork for new treatment modalities for menopause-indued KOA and (Specific Aim 2). Specific Aim 1: A component of E3 ubiquitin ligase was recently identified in a GWAS meta-analysis as a unique contributor to OA in women. As such, I will interrogate the role of estradiol-regulated, ubiquitin proteolysis in mediating menopause-induced KOA using our VCD menopause model. Changes in ubiquitin proteolysis signaling across perimenopause, menopause, and with estradiol treatment will be quantified both in vivo and in vitro. We hypothesize that (1) menopause induction will disrupt ubiquitin proteolysis activity and (2) estradiol treatment started early in menopause will restore ubiquitin proteolysis signaling and ultimately quinch menopausal KOA. Specific Aim 2: I will design an estradiol-regulated controls circuit to modulate a gene of interest (GOI) in vitro. A significant drop in estradiol is a principal physiological change associated with menopause, and an estradiol- repressed promoter will be designed to turn the circuit on. GOI candidates will be generated from previous studies and will be systematically tested to determine ideality for mediating chondrogenicity. We hypothesize that a genetic controls circuit modulated by estradiol will attenuate chondrocyte health in vitro. Impact: To support my fellowship, I have assembled a multidisciplinary team with expertise in KOA, menopause, aging, and synthetic biology. I have strategized with my mentoring team to design a rigorous training plan that will take advantage of the extraordinary research environments offered at my sponsor’s new institution (Spaulding Rehabilitation, Harvard Medical School) and the University of Pittsburgh, where I remain a full-time student. This fellowship will propel me towards my long-term goals of being a physician-scientist who practices orthopedic surgery and research leader in joint diseases and injuries presenting in women.

项目总结/摘要 背景：截至2020年，估计有6.541亿成年人患有膝关节骨关节炎（KOA）， 绝经后妇女患膝关节骨性关节炎的可能性几乎是男性的两倍。尽管如此，大多数动物 关于KOA的研究仅包括男性，在利用女性的少数研究中，绝经期通常不包括在内， 因为这不是非灵长类动物自然发生的过程。因此，缺乏针对 了解绝经期相关KOA的机制，以及相应的缺乏治疗 专门针对绝经后KOA患者的干预措施。作为我的博士工作的一部分，到目前为止， 通过向中年雌性小鼠注射4- 乙烯基环己烯二环氧化物（VCD）。我已证实该模型显示绝经期表型，包括 这些小鼠表现出比年龄匹配的未绝经小鼠更严重的KOA。 本研究的目的是探讨更年期诱发KOA的机制， 我们的VCD模型（具体目标1），并采用合成生物学技术为新的 绝经期诱发KOA的治疗方式和（具体目标2）。 具体目标1：最近在GWAS荟萃分析中鉴定出E3泛素连接酶的一种组分， 女性OA的贡献者。因此，我将询问雌二醇调节的泛素蛋白水解在 使用VCD绝经模型介导绝经诱导的KOA。泛素蛋白水解的变化 在围绝经期、绝经期和雌二醇治疗时的信号传导将在体内和体内进行定量。 体外我们假设：（1）绝经诱导会破坏泛素蛋白水解活性，（2） 在绝经早期开始的雌二醇治疗将恢复泛素蛋白水解信号传导， 绝经期膝关节炎。 具体目标2：我将设计一个雌二醇调控的控制电路，在体外调控一个感兴趣的基因（GOI）。 雌二醇的显著下降是与绝经有关的主要生理变化，雌二醇- 受抑制的启动子将被设计为打开电路。GOI候选者将从先前的启动子中产生。 研究，并将系统地测试，以确定理想的调解软骨。我们假设 由雌二醇调节的遗传控制回路将在体外削弱软骨细胞的健康。 影响：为了支持我的奖学金，我组建了一个多学科团队，他们在KOA，更年期， 衰老和合成生物学我和我的指导团队制定了一个严格的培训计划， 我将充分利用我的赞助人的新机构提供的非凡的研究环境 （斯波尔丁康复，哈佛医学院）和匹兹堡大学，在那里我仍然是一个全职的 学生.这个奖学金将推动我实现我的长期目标，成为一名医生，科学家， 整形外科和研究领导人在关节疾病和损伤的妇女提出。