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

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

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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.

伊丽莎白·伦迪纳·罗迪（Elizabeth Rendina-Ruedy）博士目前担任医学助理教授在范德比尔特骨骼生物学中心（VCBB）中，该中心是临床划分的组成部分范德比尔特大学医学中心（VUMC）药理学。她的培训和研究已有13年以上我们深深地植根于骨骼生物学，重点是营养生物化学。而研究策略在此应用中概述的将利用这些优势和兴趣，一个更加分子，提出了跨学科方法来确定骨液滴在骨液中的代谢功能细胞。因此，Rendina-Ruedy博士的心理团队Jeff Rathmell博士和Cliff Rosen博士代表这两个领域的整合，同时为候选人提供无可挑剔的支持和指导。申请人她的导师制定了一个个性化的计划，包括结构化活动增强她的研究职业，包括：心理群众联系；增强研究技能，方法，和专业知识；参与课程，讲习班和培训课程；而且，研究的传播知道。此外，VUMC提供了一个卓越的生物医学研究环境以及致力于心理初级科学家的支持人员。研究计划扩展了初步 Rendina-Ruedy博士在博士培训期间提出的发现，这表明了骨状骨 - 祖细胞在饮食引起的2型糖尿病的肥胖小鼠模型中积累了脂质液滴（T2DM）。这些数据还对应于较低的取消骨体积和减少成骨细胞生成。考虑到T2DM的临床表现为与骨折风险的增加有关，与骨矿物质密度无关（BMD）以及降低在骨形成中。综上所述，在当前应用中测试的假设是（1）细胞内脂质液滴脂解通过寄生虫通过增强成骨细胞分化来支持骨形成通过能量基材的产生和利用；（2）骨骼形成在肥胖症中受到损害相关的代谢发展，例如T2DM，由于脂肪症受损。这些假设将是通过整合创新的脉冲式追踪，共定位实验（特定的目标1A）以及确定骨髓基质细胞中代谢燃料依赖性和柔韧性（特定AIM 1B）。此外，我们将生成一个新型的条件性钙蛋白（PLIN）-2淘汰，靶向骨 - 促进蛋白细胞（PRX1-CRE）是通过上调脂解的一种手段来免受饮食诱导的肥胖症的损害。在摘要，Rendina-Ruedy博士的拟议项目代表了该领域的一个非常重要的研究问题骨骼生物学的研究将通过整合创新的代谢策略来研究。最终，这些数据寻求对增加裂缝风险增加的分子机制有更深入的了解与肥胖相关的代谢扰动（例如T2DM）相关，并可能影响未来的疗法。