Impaired Lipophagy and Lipid Droplet Accumulation in Osteoblasts

伊丽莎白·伦迪娜-鲁迪博士目前担任医学助理教授一职。 范德比尔特骨生物学中心(VCBB)，这是临床部的一个组成部分 范德比尔特大学医学中心(VUMC)的药理学。她13年多的训练和研究已经 扎根于骨生物学，侧重于营养生物化学。而研究策略 本申请中概述的将利用这些优势和兴趣，更多的分子， 提出了一种跨学科的方法来确定骨祖细胞脂滴的代谢功能。 细胞。因此，伦迪娜-鲁迪博士的导师团队，杰夫·拉斯梅尔博士和克里夫·罗森博士，是 两个领域的整合，同时为候选人提供无懈可击的支持和指导。申请人 她的导师已经制定了一个个性化的计划，包括有组织的活动，这些活动将显著 加强她的研究事业，包括：导师与学员的联系；提高研究技能、方法、 和专门知识；参与课程、讲习班和培训班；以及传播研究 和知识。此外，VUMC提供了卓越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。研究计划在初步的基础上扩展。 Rendina-Ruedy博士在她的博士培训期间所做的发现，它证明了骨衬骨质- 饮食诱导的肥胖小鼠2型糖尿病模型中祖细胞积聚脂滴 (T2 DM)。这些数据也对应于松质骨体积的减少和 成骨细胞的形成。考虑到T2 DM的临床表现是 与骨折风险增加有关，与骨密度(BMD)无关，同时伴随着下降 在骨骼形成方面。综上所述，当前应用中正在测试的假设是：(1) 细胞内脂滴脂解通过促进成骨细胞分化支持骨形成 通过产生和利用能量底物；以及(2)肥胖患者的骨骼形成受到影响-- 相关的代谢紊乱，如T2 DM，由于脂噬功能受损。这些假设将是 通过整合创新的脉冲追逐、共同本地化实验(具体目标1A)以及 确定骨髓基质细胞对代谢燃料的依赖性和灵活性(特定目标1B)。 此外，我们将产生一种新的针对骨祖细胞的条件性Perilipin(Plin)-2敲除 (PRX1-Cre)作为一种保护饮食诱导的肥胖的手段，通过上调脂解作用在骨骼中的妥协。在……里面 总而言之，Rendina-Ruedy博士提出的项目代表了该领域中一个非常重要的研究问题 将通过整合创新的新陈代谢策略来研究骨生物学。最终，这些数据 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有关，如T2 DM，并可能影响未来的治疗。

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.