Defining the relationship between attenuated insulin receptor signaling and fibrosis in diabetic tendinopathy

确定糖尿病肌腱病中胰岛素受体信号减弱与纤维化之间的关系

• 批准号: 9108008
• 负责人: Alayna Loiselle
• 金额: $ 12.17万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9108008
• 关键词: Accounting; Adhesions; Affect; Anatomy; Articular Range of Motion; Attenuated; Biology; Biomechanics; Carpal Tunnel Syndrome; Cell Proliferation; Cells; Collagen; Collagen Fiber; Complex; Complication; Data; Development; Development Plans; Diabetic mouse; Diet; Digit structure; Disease Progression; Educational Curriculum; Evaluation; Extracellular Matrix; Fat-Restricted Diet; Fibrosis; Fingers; Flexor; Gene Expression; Generations; Genetic Models; Hand; Healed; High Fat Diet; Homeostasis; Human; Image; Immunohistochemistry; Impaired wound healing; Impairment; In Vitro; Inflammatory; Insulin; Insulin Receptor; Knowledge; Laboratories; MAP Kinase Gene; Matrix Metalloproteinases; Measures; Mechanics; Mediating; Mediator of activation protein; Mentored Research Scientist Development Award; Mentorship; Messenger RNA; Metabolic; Modeling; Molecular; Movement; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Pathway interactions; Patients; Phase; Phenotype; Population; Process; Property; Receptor Signaling; Regimen; Research Personnel; Research Project Grants; Research Training; Role; Rupture; Syndrome; Tendinopathy; Tendon Injuries; Tendon structure; Tenosynovitis; Testing; Thick; Tissues; Training; Training Activity; Training Programs; Western Blotting; base; career; career development; diabetic; diabetic patient; experience; fasting blood glucose level; feeding; hand dysfunction; healing; impaired glucose tolerance; improved; improved functioning; injury and repair; insulin sensitivity; migration; mouse model; non-diabetic; novel; novel therapeutic intervention; novel therapeutics; patient population; programs; public health relevance; repaired; research and development; research study; restoration; second harmonic; success; translational approach

 DESCRIPTION (provided by applicant): This NIAMS K01 Mentored Research Scientist Development Award application outlines the career development plan and research training activities that will facilitate Dr. Alayna Loiselle's development in to a successful independent investigator in the field of diabetic tendinopathy. Drs. Hani Awad, Edward Schwarz and Robert Mooney will provide mentorship and training to enhance Dr. Loiselle's expertise in basic tendon biology and the impact of type II diabetes mellitus (T2DM) on tendon homeostasis and repair. Together we have created an integrated training plan that incorporates didactic training focused on tendon biology, T2DM and insulin receptor (IR) signaling, as well as professional development training in grantsmanship, and laboratory management; research training will include the use of cutting-edge imaging to assess collagen organization during disease progression, the use of complex mouse genetic models which will answer fundamental questions regarding the cell populations involved in flexor tendon (FT) homeostasis and repair, and the function of IR signaling in these processes. We have also established clear hallmarks of success for each training component. This program will be used to test the overall hypothesis that loss of IR signaling in FT cells results in suppressed matrix remodeling and increased fibrosis in diabetic tendons. This hypothesis is based on our preliminary data, which demonstrates suppressed IR signaling in T2DM tendons, concurrent with loss of FT gliding function and impairments in strength. These pathological tendon changes in the murine model of T2DM recapitulate the changes that are seen clinically as part of the `diabetic hand syndrome' in which FTs become fibrotic and are unable to smoothly glide through the synovial sheath. Impaired FT gliding impedes flexion of the fingers, which can compromise the function of the entire hand. In addition, diabetic tendons are more prone to rupture, which further complicates the already challenging repair of FTs; up to 40% of non-diabetic FT repairs heal with significant complications including the formation of adhesions between the tendon and synovial sheath, resulting in loss of gliding function. Healing is further impaired in diabetic patients, indicating the need to understand the cellular and molecular changes in both disrupted FT homeostasis and impaired healing in T2DM in order to identify novel therapeutic approaches to restore FT function in this rapidly expanding patient population. In the present study we will define the effects of T2DM on FT homeostasis and healing, and identify attenuated IR signaling as the primary mechanism of diabetic tendinopathy. We will also use ex-vivo and in vitro approaches to identify suppression of matrix metalloproteinase activity as a mechanism of impaired matrix remodeling and tendon fibrosis. This training program will provide Dr. Loiselle with intensive training in the effects of T2DM on tendon, but will also result in the generation of novel preliminary data, which will act as a platform for Dr. Loiselle's future research program focused on translational approaches to maintaining FT function and improving healing in the context of T2DM.

 描述（由应用程序提供）：此NIAMS K01指导研究科学家发展奖的应用程序概述了职业发展计划和研究培训活动，该活动将支持Alayna Loiselle博士的发展，以成功地为糖尿病性腱病领域的成功独立研究者。 Hani Awad博士，爱德华·施瓦茨（Edward Schwarz）和罗伯特·穆尼（Robert Mooney）将提供精神训练和培训，以增强Loiselle博士在基本肌腱生物学方面的专业知识，以及II型糖尿病（T2DM）对肌腱稳态和修复的影响。我们共同制定了一项综合培训计划，该计划结合了专注于肌腱生物学，T2DM和胰岛素受体（IR）信号的教学培训，以及助学士技巧和实验室管理方面的专业发展培训；研究培训将包括使用尖端成像来评估疾病进展过程中的胶原蛋白组织，使用复杂的小鼠遗传模型，这些模型将回答有关屈肌肌腱（FT）稳态和修复的细胞种群的基本问题，以及在这些过程中IR信号的功能。我们还为每个培训组成部分建立了明显的成功标志。该程序将用于检验总体假设，即FT细胞中IR信号丢失会导致抑制基质重塑和糖尿病肌腱纤维化的增加。该假设基于我们的初步数据，该数据证明了T2DM肌腱中的IR信号被抑制，同时也与FT滑动功能和强度损害的丧失同时抑制。 T2DM鼠模型中的这些病理肌腱变化概括了临床上被视为“糖尿病手综合征”一部分的变化，其中FTS变得纤维化，无法平滑地穿过滑膜。 ft滑行受损会阻碍手指的屈曲，这会损害整个手的功能。此外，糖尿病肌腱更容易破裂，这进一步使FTS的挑战修复变得复杂。多达40％的非糖尿病FT修复愈合，并有明显的并发症，包括肌腱和滑膜之间的粘附形成，从而导致滑行功能的丧失。糖尿病患者的愈合进一步损害，表明需要了解破坏的FT稳态和T2DM中愈合受损的细胞和分子变化，以确定在这一快速扩大的患者人群中恢复FT功能的新型治疗方法。在本研究中，我们将定义T2DM对FT稳态和愈合的影响，并确定衰减的IR信号是糖尿病诱导的主要机制。我们还将使用前体体和体外方法来识别基质金属蛋白酶活性的抑制作用，作为基质重塑和肌腱纤维化受损的机制。该培训计划将为Loiselle博士提供T2DM对肌腱影响的深入培训，但也将导致产生 新型初步数据将充当Loiselle博士未来研究计划的平台，该计划着重于转化方法，以维持FT功能并在T2DM的背景下改善愈合。