Impaired Lipophagy and Lipid Droplet Accumulation in Osteoblasts

伊丽莎白·伦迪娜-鲁迪博士目前是缅因州医学研究中心的高级博士后研究员 克利福德·J·罗森博士的实验室里。她13年多的训练和研究深深植根于 骨生物学，重点是营养生物化学。虽然本报告中概述的研究战略 应用程序将利用这些优势和兴趣，更加分子，跨学科 提出了测定中性脂滴在骨祖细胞中代谢功能的方法。AS 就这样，伦迪娜-鲁迪博士的导师团队，罗森博士和迈克尔·P·捷克博士，集中体现了 两个领域，同时也为候选人在过渡到 独立调查员。申请者和她的导师已经制定了一个个性化的计划，包括 将显著促进她的研究事业的有组织的活动，包括：相当多的导师-辅导者 联系；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；以及传播研究和知识。此外，MMCRI还提供了 卓越的生物医学研究环境，以及致力于促进 年轻的科学家。研究计划扩展了伦迪娜-鲁迪博士在她的研究期间所做的初步发现 博士训练表明，骨衬里的骨祖细胞在 饮食诱导的2型糖尿病肥胖小鼠模型。这些数据也与较低的 松质骨体积和成骨细胞生成减少。这些数据特别令人感兴趣 T2 DM的临床表现与骨折风险的增加有关，与骨骼无关 矿物质密度(BMD)，伴随着骨形成的减少。综上所述，这些假说正在被检验 目前的应用是：(1)细胞内的脂滴通过脂溶作用支持骨形成 通过产生和利用能量底物促进成骨细胞分化；以及(2) 在肥胖相关的代谢紊乱中，如T2 DM，骨形成受到损害 吞脂性。这些假设将通过整合创新的脉冲追逐、共同本地化来解决 实验(特定目标1A)，以及确定骨髓中代谢燃料的依赖性和灵活性 基质细胞(特异性靶点1B)。此外，我们还将产生一种新的条件性Perilipin(Plin)-2敲除， 靶向骨祖细胞(PRX1-CRE)作为一种保护饮食诱导的肥胖妥协的手段 通过上调脂滴对骨骼的脂解作用。总而言之， 伦迪纳-鲁迪博士提出的项目， 罗森博士和捷克博士的指导，代表着骨骼领域一个非常重要的研究问题 将通过整合创新的脂质生物学策略来研究这一生物学。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 is currently a senior postdoctoral fellow at the Maine Medical Center Research Institute in Dr. Clifford J. Rosen's laboratory. 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 neutral lipid droplets in osteo-progenitor cells. As such, Dr. Rendina-Ruedy's mentor team, Dr. Rosen and Dr. Michael P. Czech, epitomize the integration of the two fields, while also providing impeccable support and guidance to the candidate during her transition to an independent investigator. The applicant and her mentors have developed an individualized plan to include structured activities that will significantly enhance her research career, including: considerable mentor-mentee contact; enhancing research skills, methodologies, and expertise; involvement in courses, workshops, and training sessions; and, the dissemination of research and knowledge. Additionally, MMCRI offers an exceptional biomedical research environment, as well as supportive staff that are committed to promoting young 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 lipid droplet lipolysis. In summary, Dr. Rendina-Ruedy's proposed project, under the mentorship of Drs. Rosen and Czech, represents a highly significant research problem in the field of bone biology that will be investigated by integrating innovative lipid biology 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.