Muscle ­bone interaction and its role in diabetic bone disease of Type I diabetes

摘要 观察到1型糖尿病(T1D)患者的骨折发生率比 普通民众。糖尿病骨骼疾病的负担部分是由于缺乏证据支持 有针对性的预防和干预措施，以减少该人群中的骨折。此外，患有T1D的人 表现出骨骼肌功能障碍，伴随着肌肉力量和肌肉质量的下降。骨骼 肌肉和骨骼的沟通是一个潜在的可修改因素，可能有助于糖尿病的发展 肌肉骨骼疾病。更具体地说，候选人提出一种名为myostatin的肌肉因子直接 参与糖尿病骨疾病的发展，并可能与骨骼肌功能障碍有关。这个 肌肉抑制素在T1D中的作用以及它如何在这种疾病中影响肌肉骨骼系统是知识上的空白。 这项提案将解决这一问题。具体地说，这项建议的三个目标是：1.量化 慢性骨质疏松症患者血清和骨骼肌中肌生长抑素水平与骨参数的关系 不含T1D；2.量化血清、肌肉和骨骼中的肌肉生长抑素水平 胰岛素缺乏性糖尿病小鼠的表型；3.评价抑制肌肉生长抑素是否有益于 预防胰岛素缺乏性糖尿病的DBD；最后4：确定肌肉生长抑素的作用机制 在正常血糖和高血糖条件下对成骨细胞的影响。肌肉抑制素，它被认为是 对骨骼和骨骼肌都有负面影响，可以作为肌肉骨骼功能的标志和 T1D患者骨折风险的替代者。此外，它可能会提供一个有针对性的机会 预防或改善与T1D相关的肌肉骨骼功能障碍的干预。所获得的知识 这些研究将为未来糖尿病肌肉骨骼健康的研究奠定基础，并将提供 候选人有机会过渡到上述领域的独立职业生涯。 这项建议提出了一个为期五年的研究职业发展计划，重点是研究 1型糖尿病中肌肉和骨骼的相互作用；具体地说，肌肉如何派生分子，称为 肌肉激动素导致糖尿病骨疾病，这是1型糖尿病的一种严重和新出现的并发症。这个 候选人目前在儿科分部担任儿科学助理教授 肯塔基大学内分泌学博士。她有75%的受保护时间用于研究、独立办公室 空间、实验室空间以及巴恩斯泰伯·布朗糖尿病公司提供的所有设备和资源 中心。应聘者致力于肌肉骨骼研究领域的学术生涯 她患有糖尿病，并得到了她的导师和她的部门的支持。拟议的研究和补充 教学工作将为应聘者提供基础、翻译和临床研究方面的研究技能 使其能够过渡到独立的临床科学家。

Summary Bone fracture incidence observed in individuals with Type 1 diabetes (T1D) is much higher compared to the general population. The burden of diabetic bone disease is partially due to lack of evidence to support targeted prevention and interventions to reduce fractures in this population. Furthermore, those with T1D exhibit skeletal muscle dysfunction associated with decreased muscle strength and muscle mass. Skeletal muscle and bone communication is a potential modifiable factor that may contribute to development of diabetic musculoskeletal disease. More specifically, the candidate proposes that a myokine called myostatin, is directly involved in development of diabetic bone disease and may associate with skeletal muscle dysfunction. The role of myostatin in T1D and how it affects the musculoskeletal system in this disease are gaps in knowledge that will be addressed with this proposal. Specifically, the three aims of this proposal are: 1. Quantify the relationship between myostatin levels in serum and skeletal muscle, and bone parameters of humans with and without T1D; 2. Quantify the relationship between myostatin levels in serum and muscle and the bone phenotype of mice with insulin-deficient diabetes; 3. Evaluate whether inhibition of myostatin is beneficial for prevention of DBD in insulin-deficient diabetes; and lastly 4: Determine the mechanism of action of myostatin on osteoblastic bone cells under normoglycemic and hyperglycemic conditions. Myostatin, which is thought to negatively affect both bone and skeletal muscle, may serve both as a marker of musculoskeletal function and surrogate for risk for fracture in those with T1D. Additionally, it may offer an opportunity for targeted intervention to prevent or improve musculoskeletal dysfunction associated with T1D. The knowledge gained from these studies will set the ground for future studies in musculoskeletal health in diabetes and will offer the candidate an opportunity to transition towards an independent career in the abovementioned field. This proposal presents a five-year research career development program focused on the study of muscle and bone interactions in Type 1 diabetes; and specifically, how muscle derived molecules, called myokines contribute to diabetic bone disease, a serious and emerging complication of Type 1 diabetes. The candidate currently holds a position as an Assistant Professor of Pediatrics in the Division of Pediatric Endocrinology at the University of Kentucky. She has 75% protected time for research, independent office space, laboratory space and access to all equipment and resources offered by the Barnstable Brown Diabetes Center. The candidate is strongly committed to an academic career in the field of musculoskeletal research in diabetes and is supported by her mentors and her department. The proposed study and the complementary didactic work will provide the candidate with research skills in basic, translational and clinical research thereby enabling to transition to an independent clinician scientist.