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

• 批准号: 10192660
• 负责人: Elizabeth Rendina-Ruedy
• 金额: $ 9.34万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192660
• 关键词: Address; Adenosine Triphosphate; Adipocytes; Adolescent; Adult; Affect; Amino Acids; Animals; Biology; Biomedical Research; Bone Density; Bone Marrow; Cell Respiration; Cells; Child; Clinical; Data; Defect; Dependence; Diet; Educational workshop; Environment; Equation; Exhibits; Fatty Acids; Fracture; Functional disorder; Future; Generations; Glucose; Glutamine; Glycolysis; Goals; High Fat Diet; Homeostasis; Hyperglycemia; Impairment; Intracellular Accumulation of Lipids; Investigation; Knock-out; Knowledge; Label; Laboratories; Lead; Lipids; Lipolysis; Lysosomes; Maine; Marrow; Mathematics; Measures; Medical center; Mentors; Mentorship; Metabolic; Metabolic Pathway; Methodology; Minerals; Mitochondria; Modeling; Molecular; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nutritional Biochemistry; Obesity; Osteoblasts; Osteogenesis; Oxidative Phosphorylation; Pathology; Phase; Phenotype; Physiologic pulse; Plant Roots; Postdoctoral Fellow; Production; Public Health; Pyruvate; Research; Research Institute; Research Personnel; Role; Scientist; Skeleton; Source; Stromal Cells; Structure; Techniques; Testing; Training; Vacuole; Vesicle; base; body system; bone; bone cell; bone fragility; bone health; bone metabolism; bone quality; career; comorbidity; conditional knockout; design; diabetic patient; diet-induced obesity; experimental study; flexibility; fracture risk; impaired glucose tolerance; innovation; interest; mineralization; mouse model; novel; obese person; osteoblast differentiation; osteoprogenitor cell; perilipin; preference; progenitor; skeletal; skills; substantia spongiosa; transdifferentiation

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.

Elizabeth Rendina-Ruedy 博士目前是缅因州医学中心研究中心的高级博士后研究员 研究所位于 Clifford J. Rosen 博士的实验室。她13年多的培训和研究已经深深植根于 骨生物学，重点是营养生物化学。虽然本文概述的研究策略 应用程序将利用这些优势和兴趣，一种更加分子化、跨学科的 提出了确定骨祖细胞中中性脂滴的代谢功能的方法。作为 因此，Rendina-Ruedy 博士的导师团队 Rosen 博士和 Michael P. Czech 博士体现了 两个领域，同时还在候选人过渡到候选人的过程中提供无可挑剔的支持和指导 独立调查员。申请人和她的导师制定了个性化计划，其中包括 结构化的活动将显着提高她的研究生涯，包括： 接触;提高研究技能、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 卓越的生物医学研究环境，以及致力于促进生物医学研究的支持人员 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，证明骨衬骨祖细胞在 饮食诱导的 2 型糖尿病（T2DM）肥胖小鼠模型。这些数据也对应了较低的 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 T2DM 的临床表现与骨折风险增加相关，与骨量无关 矿物质密度（BMD），同时骨形成减少。综合起来，正在检验的假设 目前的应用是（1）通过自噬作用的细胞内脂滴脂肪分解支持骨形成 通过能量底物的产生和利用来增强成骨细胞分化；和（2） 在与肥胖相关的代谢紊乱（如 T2DM）中，骨形成受到损害，这是由于骨形成受损 脂肪自噬。这些假设将通过整合创新的脉冲追踪、共定位来解决 实验（具体目标 1A），以及确定骨髓的代谢燃料依赖性和灵活性 基质细胞（具体目标 1B）。此外，我们将生成一种新型条件性周脂蛋白 (Plin)-2 敲除， 以骨祖细胞 (Prx1-Cre) 为靶点，作为预防饮食诱导的肥胖损害的一种手段 通过上调脂滴脂肪分解来增强骨骼。总之， Rendina-Ruedy 博士提出的项目，根据 博士的指导。罗森和捷克代表了骨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生物学。最终，这些数据旨在 更好地了解骨折风险增加的分子机制 与肥胖相关的代谢紊乱（例如 T2DM）相关，并可能影响未来的治疗。