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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在范德比尔特骨生物学中心（VCBB），这是临床医学部的一个组成部分，范德比尔特大学医学中心（VUMC）药理学。她13年多的培训和研究，它深深植根于骨生物学，重点是营养生物化学。虽然研究策略在本申请中概述的将利用这些优势和兴趣，一个更分子，提出了一种跨学科的方法来确定脂滴在骨祖细胞中的代谢功能细胞因此，Rendina-Ruedy博士的导师团队Jeff拉斯梅尔博士和Cliff罗森博士是这两个领域的融合，同时为候选人提供无可挑剔的支持和指导。申请人她的导师们已经制定了一个个性化的计划，包括结构化的活动，提高她的研究生涯，包括：导师与学员的联系;提高研究技能，方法，参与课程、讲习班和培训班;以及传播研究成果和知识此外，VUMC提供了一个特殊的生物医学研究环境，以及致力于指导初级科学家的支持性工作人员。该研究计划扩大了初步的 Rendina-Ruedy博士在博士培训期间的研究结果表明，在饮食诱导的2型糖尿病肥胖小鼠模型中祖细胞积累脂滴（2型糖尿病）。这些数据也与松质骨体积降低和成骨细胞生成这些数据特别令人感兴趣，因为T2 DM的临床表现与骨折风险增加相关，与骨矿物质密度（BMD）无关，沿着降低在骨骼形成中。综上所述，在本申请中测试的假设是（1）细胞内脂滴脂解通过促进成骨细胞分化支持骨形成通过能量底物的产生和利用;和（2）骨形成在肥胖症中受到损害- 相关的代谢紊乱，如T2 DM，由于受损的脂肪吞噬。这些假设将是通过整合创新的脉冲追踪、共定位实验（具体目标1A）以及确定骨髓基质细胞中的代谢燃料依赖性和灵活性（具体目标1B）。此外，我们将产生一种新的条件性周脂蛋白（Plin）-2敲除，靶向骨祖细胞（Prx 1-Cre）作为一种手段，通过上调脂解来保护骨骼免受饮食诱导的肥胖损害。在总之，Rendina-Ruedy博士提出的项目代表了该领域一个非常重要的研究问题将通过整合创新的代谢策略来研究骨生物学。最终，这些数据寻求提供一个更好的理解的分子机制的基础上增加骨折的风险与肥胖相关的代谢紊乱相关，如T2 DM，并可能影响未来的治疗。