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

 描述(由申请者提供)：这份NIAMS K01指导研究科学家发展奖申请概述了职业发展计划和研究培训活动，这些活动将促进Alayna Loiselle博士发展成为糖尿病肌腱病领域的一名成功的独立研究员。Hani Awad博士、Edward Schwarz博士和Robert Mooney博士将提供指导和培训，以增强Loiselle博士在基本肌腱生物学以及II型糖尿病(T2 DM)对肌腱稳态和修复的影响方面的专业知识。我们共同创建了一个集成的培训计划，其中包括专注于肌腱生物学、T2 DM和胰岛素受体(IR)信号的授课培训，以及大专技能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组织，使用复杂的小鼠遗传模型来回答有关屈肌腱(FT)动态平衡和修复所涉及的细胞群体以及IR信号在这些过程中的功能等基本问题。我们还为每个培训部分确立了明确的成功标志。这个程序将被用来检验这一总体假设，即FT细胞中IR信号的丢失会导致糖尿病肌腱基质重塑受抑和纤维化增加。这一假说是基于我们的初步数据，这些数据表明T2 DM肌腱IR信号受到抑制，同时伴有FT滑动功能的丧失和力量的损害。在T2 DM的小鼠模型中，这些病理肌腱变化概括了临床上被视为糖尿病手综合征的一部分的变化，在这种情况下，FTs变得纤维化，不能顺利穿过滑膜鞘。FT滑动功能受损会阻碍手指的屈曲，这可能会损害整个手的功能。此外，糖尿病肌腱更容易断裂，这使本已具有挑战性的FTs修复工作变得更加复杂；高达40%的非糖尿病FT修复术后愈合时会出现重大并发症，包括在肌腱和滑膜鞘之间形成粘连，导致滑行功能丧失。糖尿病患者的修复功能进一步受损，这表明有必要了解T2 DM患者FT动态平衡受损和愈合受损的细胞和分子变化，以确定在这一快速增长的患者群体中恢复FT功能的新治疗方法。在本研究中，我们将确定T2 DM对FT动态平衡和愈合的影响，并确定IR信号减弱是糖尿病肌腱病变的主要机制。我们还将使用体外和体外方法来确定基质金属蛋白酶活性的抑制是受损的基质重塑和肌腱纤维化的机制。该培训计划将为Loiselle博士提供关于T2 DM对肌腱影响的强化培训，但也将导致 新的初步数据，这将作为Loiselle博士未来研究计划的平台，重点关注在T2 DM背景下维持FT功能和改善愈合的翻译方法。

 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.