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

肌骨相互作用及其在 I 型糖尿病骨病中的作用

基本信息

批准号：
10358516
负责人：
Evangelia Kalaitzoglou
金额：
$ 16.45万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10358516
关键词：
20 year old Activin Receptor Address Affect Age Animal Model Antibodies Basic Science Biopsy Bone Density Bone Marrow Stem Cell Bone Resorption Cell Line Cells Childhood Clinical Clinical Research Communication Complication Complications of Diabetes Mellitus Data Development Diabetes Mellitus Disease Endocrine Endocrinology Environment Equipment Exhibits FRAP1 gene Foundations Fracture Functional disorder Future GDF8 gene Gene Expression Gene Proteins General Population Genes Health Hip Fractures Hip region structure Human Hyperglycemia Impairment In Vitro Incidence Individual Insulin Insulin-Dependent Diabetes Mellitus Intervention Kentucky Knowledge Laboratories Lead Life MAP Kinase Gene Measures Mechanics Mediating Mediator of activation protein Mentors Mus Muscle Muscle function Musculoskeletal Musculoskeletal Diseases Musculoskeletal System Nurses&apos Health Study Osteoblasts Osteocalcin Osteocytes Osteogenesis Outcome Pathway interactions Pediatrics Pharmacology Phenotype Physical Capacity Population Population Study Positioning Attribute Prevalence Prevention Program Development Relative Risks Research Resources Risk Roentgen Rays Role Sampling Scientist Serum Signal Pathway Signal Transduction Skeletal Muscle Skeletal bone Time Trabecular Bone Score Translational Research Universities Upper Extremity Fracture Work bone bone cell bone fracture repair bone imaging bone mass bone turnover career career development clinically significant cost diabetic diabetic bone disease diabetogenic fracture risk high risk improved in vivo mineralization mouse model muscle form negative affect novel osteoblast differentiation paracrine prevent professor prospective receptor reduced muscle mass reduced muscle strength skills young adult

项目摘要

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.

概括与1型糖尿病患者（T1D）中观察到的骨断裂发生率相比普通人群。糖尿病骨病的负担部分是由于缺乏支持的证据有针对性的预防和干预措施减少该人群的骨折。此外，那些带有T1D的人表现出与肌肉力量降低相关的骨骼肌功能障碍。骨骼肌肉和骨交流是可能有助于糖尿病发展的潜在可修改因素肌肉骨骼疾病。更具体地说，候选人提出一种称为肌生抑素的肌动物，直接参与糖尿病骨病的发展，并可能与骨骼肌功能障碍相关。这 Myostatin在T1D中的作用及其如何影响该疾病的肌肉骨骼系统是知识的差距这将通过此提案解决。具体而言，该提案的三个目标是：1。量化血清和骨骼肌中肌生抑素水平之间的关系，以及人类的骨头参数与没有T1D； 2。量化血清和肌肉与骨骼中肌生抑素水平之间的关系胰岛素缺陷糖尿病的小鼠表型； 3。评估抑制肌抑制素是否有益胰岛素缺陷糖尿病中的DBD预防；最后4：确定肌抑制素的作用机理在正常血糖和高血糖条件下的成骨细胞细胞上。肌汀，被认为是负面影响骨骼和骨骼肌，既可以用作肌肉骨骼功能的标志 T1D患者的骨折风险替代。此外，它可能为目标提供机会干预以预防或改善与T1D相关的肌肉骨骼功能障碍。知识获得了从这些研究中将为糖尿病中肌肉骨骼健康的未来研究奠定基础，并将提供候选人有机会过渡到上述领域的独立职业。该建议提出了一项五年研究职业发展计划，重点是研究 1型糖尿病中的肌肉和骨相互作用；具体而言，肌肉衍生分子如何称为肌动物有助于糖尿病骨病，这是1型糖尿病的严重而新兴的并发症。这候选人目前担任小儿分工的儿科助理教授肯塔基大学的内分泌学。她有75％的研究时间，独立办公室空间，实验室空间以及可访问Barnstable棕色糖尿病提供的所有设备和资源中心。候选人强烈致力于从事肌肉骨骼研究领域的学术生涯糖尿病，并得到她的导师和部门的支持。拟议的研究和补充教学工作将为候选人提供基础，翻译和临床研究的研究技能能够过渡到独立的临床医生。