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的高级博士后研究员 Clifford J. Rosen博士的实验室研究所。她的13年以上的培训和研究已深深地扎根 骨生物学，重点是营养生物化学。虽然研究策略概述了 应用将利用这些优势和兴趣，这是一个更加分子，跨学科的 提出了方法来确定骨促进剂细胞中中性脂质液滴的代谢功能。作为 像Rendina-Ruedy博士的导师团队Rosen博士和Michael P. Czech博士一样，代表了整合 两个领域，同时还为候选人过渡到一个无可挑剔的支持和指导 独立研究者。申请人和她的导师制定了个性化计划，以包括 结构化的活动将大大提高她的研究职业，包括：相当大的导师奖 接触;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；并且，研究和知识的传播。此外，MMCRI提供了 非凡的生物医学研究环境以及致力于促进的支持人员 年轻科学家。研究计划扩展了Rendina-Ruedy博士在她期间的初步发现 博士训练表明，骨内骨 - 促进蛋白细胞积累了脂质液滴 2型糖尿病（T2DM）的饮食引起的肥胖小鼠模型。这些数据也对应于较低 取消骨体积和成骨细胞生成的减少。这些数据特别感兴趣 T2DM的临床表现与骨折风险的增加有关，与骨骼无关 矿物密度（BMD），以及骨形成的减少。两者一起测试了假设 在当前的应用中，（1）通过寄生虫的细胞内脂质液滴脂解支持骨形成 通过通过能量底物的产生和利用来增强成骨细胞分化； （2） 骨骼形成在与肥胖相关的代谢扰动（例如T2DM）中受到损害 脂肪。这些假设将通过整合创新的脉冲追踪，共定位来解决 实验（特定AIM 1A），以及确定骨髓中的代谢燃料依赖性和柔韧性 基质细胞（特定目标1b）。此外，我们将产生一种新颖的条件围蛋白（PLIN）-2敲出来， 针对骨促进剂细胞（PRX1-CRE），以保护饮食诱导的肥胖症的一种手段 通过上调脂质液滴脂解。总之， Rendina-Ruedy博士的拟议项目， 博士的指导。罗森（Rosen）和捷克（Czech）代表了骨骼领域的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的生物学。最终，这些数据试图 对增加裂缝风险增加的分子机制提供更深入的了解 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。