Impaired Lipophagy and Lipid Droplet Accumulation in Osteoblasts

成骨细胞中的脂质自噬和脂滴积聚受损

基本信息

批准号：
10619139
负责人：
Elizabeth Rendina-Ruedy
金额：
$ 6.16万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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：
2022-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10619139
关键词：
Academic Medical Centers Address Affect Appointment Award Biology Biomedical Research Birth Bone Density Bone Marrow COVID-19 COVID-19 impact COVID-19 pandemic Child Clinical Clinical Pharmacology Core Facility Data Daughter Dependence Disease Outbreaks Educational workshop Enrollment Ensure Environment Equipment Faculty Family Funding Future Generations Grant Home Human Resources Husband Impairment Individual Interruption K-Series Research Career Programs Knock-out Knowledge Laboratories Laboratory Research Left Light Lipids Lipolysis Maine Medical Research Medicine Mentored Research Scientist Development Award Mentors Metabolic Methodology Molecular Mouse Strains Mus National Institute of Arthritis and Musculoskeletal and Skin Diseases Non-Insulin-Dependent Diabetes Mellitus Nursery Schools Nutritional Biochemistry Obesity Occupations Osteoblasts Osteogenesis Periodicity Persons Phase Physiologic pulse Plant Roots Positioning Attribute Productivity Reagent Research Research Activity Research Assistant Research Training Safety Schedule Schools Scientist Secure Severities Shipping Social Distance Stromal Cells Structure Testing Time Training Uncertainty Virus Work animal facility bone career career development design diet-induced obesity experience experimental study flexibility fracture risk innovation interest medical schools mouse model novel operation osteoblast differentiation osteoprogenitor cell pandemic disease perilipin professor programs skills social space substantia spongiosa tenure track

项目摘要

Dr. Elizabeth Rendina-Ruedy currently maintains a faculty appointment as an Assistant Professor of Medicine in the Vanderbilt Center for Bone Biology (VCBB), which is a component of the Division of Clinical Pharmacology of Vanderbilt University Medical Center (VUMC). Her 13+ years of training and research has been deeply rooted in bone biology with an emphasis in nutritional biochemistry. While the research strategy outlined in this application will take advantage of these strengths and interests, a much more molecular, transdisciplinary approach is proposed to determine the metabolic function of lipid droplets in osteo-progenitor cells. As such, Dr. Rendina-Ruedy’s mentor team, Dr. Jeff Rathmell and Dr. Cliff Rosen, epitomize the integration of the two fields, while providing impeccable support and guidance to the candidate. The applicant and her mentors have developed an individualized plan to include structured activities that will significantly enhance her research career, including: mentor-mentee contact; enhancing research skills, methodologies, and expertise; involvement in courses, workshops, and training sessions; and, the dissemination of research and knowledge. Additionally, VUMC offers an exceptional biomedical research environment, as well as supportive staff that are committed to mentoring junior scientists. The research plan expands on preliminary findings made by Dr. Rendina-Ruedy during her doctoral training, which demonstrated that bone-lining osteo- progenitor cells accumulated lipid droplets in a diet-induced obese mouse model of type 2 diabetes mellitus (T2DM). These data also corresponded to lower cancellous bone volume and a decrease in osteoblastogenesis. These data were of particular interest given that the clinical manifestation of T2DM is associated with an increase in fracture risk, independent of bone mineral density (BMD), along with a decrease in bone formation. Taken together, the hypotheses being tested in the current application are that (1) intracellular lipid droplet lipolysis via lipophagy supports bone formation by enhancing osteoblast differentiation through the generation and utilization of energy substrates; and (2) bone formation is compromised in obesity- related metabolic derangements such as T2DM, due to impaired lipophagy. These hypotheses will be addressed by integrating an innovative pulse-chase, co-localization experiment (specific aim 1A), as well as determining metabolic fuel dependency and flexibility in bone marrow stromal cells (specific aim 1B). Additionally, we will generate a novel conditional perilipin (Plin)-2 knock out, targeted in osteo-progenitor cells (Prx1-Cre) as a means to protect from diet-induced obesity compromise in bone by up-regulating lipolysis. In summary, Dr. Rendina-Ruedy’s proposed project represents a highly significant research problem in the field of bone biology that will be investigated by integrating innovative metabolic strategies. Ultimately, these data seek to provide a greater understanding of the molecular mechanisms underlying the increased fracture risk associated with obesity related metabolic perturbations, such as T2DM, and may impact future therapies.

Elizabeth Rendina-Ruedy 博士目前担任医学助理教授范德比尔特骨生物学中心 (VCBB)，该中心是临床科的一个组成部分范德比尔特大学医学中心 (VUMC) 的药理学她经过 13 年以上的培训和研究。深深扎根于骨骼生物学，重点是营养生物化学，同时研究策略。本申请中概述的将利用这些优势和兴趣，一种更加分子化的、提出跨学科方法来确定骨祖细胞中脂滴的代谢功能因此，Rendina-Ruedy 博士的导师团队 Jeff Rathmell 博士和 Cliff Rosen 博士就是这一观点的缩影。整合两个领域，同时为候选人提供无可挑剔的支持和指导。她和她的导师制定了一项个性化计划，其中包括结构化活动，这些活动将显着增强她的研究生涯，包括：增强研究技能、方法、和专业知识；参与课程、研讨会和培训课程；以及传播研究成果；此外，VUMC 还提供卓越的生物医学研究环境以及知识。致力于指导初级科学家的支持人员该研究计划在初步基础上进行了扩展。 Rendina-Ruedy 博士在博士培训期间做出的研究结果表明，骨衬骨在饮食诱导的 2 型糖尿病肥胖小鼠模型中，祖细胞积累了脂滴（T2DM）这些数据也对应于松质骨体积的降低和骨量的减少。鉴于 T2DM 的临床表现，这些数据特别令人感兴趣。与骨折风险增加相关，与骨矿物质密度 (BMD) 无关，同时降低综上所述，当前应用中测试的假设是（1）通过自噬作用的细胞内脂滴脂肪分解通过增强成骨细胞分化来支持骨形成通过能量底物的产生和利用；(2) 肥胖导致骨骼形成受到损害- 相关的代谢紊乱，如 T2DM，由于脂肪吞噬功能受损而导致。通过集成创新的脉冲追踪、共定位实验（具体目标 1A）以及确定骨髓基质细胞的代谢燃料依赖性和灵活性（具体目标 1B）。此外，我们将生成一种新型条件性周脂蛋白 (Plin)-2 敲除，靶向骨祖细胞 (Prx1-Cre) 作为一种通过上调脂肪分解来防止饮食引起的肥胖损害的方法。总之，Rendina-Ruedy 博士提出的项目代表了该领域的一个非常重要的研究问题最终，将通过整合这些数据来研究骨生物学。寻求对骨折风险增加的分子机制有更深入的了解与肥胖相关的代谢紊乱（例如 T2DM）相关，并可能影响未来的治疗。