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

 描述（由申请人提供）：本NIAMS K 01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，将促进Alayna Loiselle博士在糖尿病肌腱病变领域成为成功的独立研究者。哈尼阿瓦德博士、爱德华施瓦茨博士和罗伯特穆尼博士将提供指导和培训，以提高Loiselle博士在基础肌腱生物学和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综合培训计划，其中包括专注于肌腱生物学，T2 DM和胰岛素受体（IR）信号传导的教学培训，以及granectin和实验室管理的专业发展培训;研究培训将包括使用尖端成像来评估疾病进展期间的胶原组织，使用复杂的小鼠遗传模型，这将回答有关屈肌腱（FT）稳态和修复中涉及的细胞群的基本问题，以及IR信号在这些过程中的功能。我们还为每个培训部分确定了明确的成功标志。该程序将用于检验FT细胞中IR信号传导的丧失导致基质重塑受抑制和糖尿病肌腱纤维化增加的总体假设。这一假设基于我们的初步数据，该数据表明T2 DM肌腱中的IR信号传导受到抑制，同时伴有FT滑动功能丧失和强度受损。T2 DM小鼠模型中的这些病理性肌腱变化概括了临床上作为“糖尿病手综合征”一部分观察到的变化，其中FT变得纤维化并且不能顺利地滑过滑膜鞘。受损的FT滑动阻碍手指的屈曲，这可能会损害整个手的功能。此外，糖尿病肌腱更容易断裂，这使已经具有挑战性的FT修复进一步复杂化;高达40%的非糖尿病FT修复愈合时伴有严重并发症，包括肌腱和滑膜鞘之间形成粘连，导致滑动功能丧失。糖尿病患者的愈合进一步受损，这表明需要了解T2 DM中FT稳态破坏和愈合受损的细胞和分子变化，以确定新的治疗方法来恢复快速扩大的患者人群中的FT功能。在本研究中，我们将确定T2 DM对FT稳态和愈合的影响，并确定IR信号减弱是糖尿病肌腱病变的主要机制。我们还将使用离体和体外的方法来确定抑制基质金属蛋白酶活性作为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T2 DM对肌腱影响的强化培训，但也将导致产生 新的初步数据，这将作为Loiselle博士未来研究计划的平台，重点是在T2 DM背景下维持FT功能和改善愈合的转化方法。

 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.