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

总结 1型糖尿病（T1 D）患者的骨折发生率远高于 普通民众。糖尿病性骨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，以减少这一人群的骨折。此外，T1 D患者 表现出与肌肉力量和肌肉质量降低相关的骨骼肌功能障碍。骨骼 肌肉和骨骼的沟通是一个潜在的可改变的因素，可能有助于糖尿病的发展， 肌肉骨骼疾病更具体地说，这位候选人提出，一种名为肌生长抑制素的肌因子， 参与糖尿病性骨疾病的发展，并可能与骨骼肌功能障碍有关。的 肌生长抑制素在T1 D中的作用以及它如何影响这种疾病中的肌肉骨骼系统是知识的空白 这一问题将在本提案中得到解决。具体而言，本提案的三个目标是：1.量化 人血清和骨骼肌中肌生长抑制素水平与骨参数之间的关系 没有T1 D; 2.定量分析血清、肌肉和骨骼中肌肉生长抑制素水平之间的关系 胰岛素缺乏型糖尿病小鼠的表型; 3.评估肌肉生长抑制素的抑制是否有益于 预防胰岛素缺乏型糖尿病中的DBD;最后4：确定肌肉生长抑制素的作用机制 对成骨细胞的影响。肌肉生长抑制素，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， T1 D患者骨折风险替代指标。此外，它还可以提供一个有针对性的机会， 预防或改善与T1 D相关的肌肉骨骼功能障碍的干预。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一个独立的职业生涯在上述领域。 该提案提出了一项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;特别是肌肉衍生分子，称为 肌因子导致糖尿病性骨疾病，这是1型糖尿病的严重和新出现的并发症。的 候选人目前担任儿科系儿科助理教授 肯塔基州大学的内分泌学。她有75%的时间用于研究，独立办公室 空间，实验室空间和使用巴恩斯特布尔布朗糖尿病提供的所有设备和资源 中心候选人坚定地致力于在肌肉骨骼研究领域的学术生涯， 糖尿病和支持她的导师和她的部门。拟议的研究和补充 教学工作将为候选人提供基础，转化和临床研究的研究技能，从而 使其能够转变为独立的临床科学家。

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.