Impaired Lipophagy and Lipid Droplet Accumulation in Osteoblasts

Elizabeth Rendina-Ruedy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。她13年以上的培训和研究已经深深扎根于 骨生物学，侧重于营养生物化学。虽然本文概述的研究策略 应用程序将利用这些优势和利益，更分子，跨学科 提出了一种测定骨祖细胞中性脂滴代谢功能的方法。作为 这样，Rendina-Ruedy博士的导师团队，罗森博士和Michael P. Czech博士，集中体现了 两个领域，同时也提供无可挑剔的支持和指导，以候选人在她过渡到一个 独立调查员申请人和她的导师已经制定了个性化的计划，包括 结构化的活动，这将大大提高她的研究生涯，包括：相当多的导师，学员 接触;提高研究技能，方法和专业知识;参与课程，研讨会， 培训课程;以及传播研究和知识。此外，MMCRI还提供 卓越的生物医学研究环境，以及致力于促进 年轻的科学家该研究计划扩展了Rendina-Ruedy博士在她的研究期间所做的初步发现。 博士培训，这表明骨衬骨祖细胞积累脂滴在一个 2型糖尿病（T2 DM）的饮食诱导的肥胖小鼠模型。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增加相关，与骨无关 骨密度（BMD），沿着骨形成减少。综合起来，被测试的假设 （1）通过脂肪吞噬的细胞内脂滴脂解支持骨形成 通过产生和利用能量底物来增强成骨细胞分化;和（2） 骨形成在肥胖相关的代谢紊乱如T2 DM中受到损害， 脂肪吞噬这些假设将通过整合创新的脉冲追踪，共同定位 实验（具体目标1A），以及确定骨髓中的代谢燃料依赖性和灵活性 基质细胞（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，以防止饮食诱导的肥胖妥协， 骨通过上调脂滴脂解。总的来说， 博士Rendina-Ruedy提出的项目，根据 罗森博士和捷克的指导，代表了骨领域一个非常重要的研究问题 生物学将通过整合创新的脂质生物学策略进行研究。最终，这些数据旨在 更深入地了解骨折风险增加的分子机制 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。

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.