s100a4 Signaling in Fibrotic Diabetic Tendon Healing

纤维化糖尿病肌腱愈合中的 s100a4 信号转导

• 批准号: 10360571
• 负责人: Alayna Loiselle
• 金额: $ 33.54万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360571
• 关键词: Acute; Animals; Attenuated; Binding; Cells; Cicatrix; Clinical; Data; Diabetic mouse; Extracellular Matrix; FDA approved; Failure; Flexor; Impaired healing; Impairment; Incidence; Individual; Inferior; Injections; Injury; Knock-out; Knowledge; Mechanics; Mediating; Mus; Myofibroblast; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Outcome; Peptides; Pharmaceutical Preparations; Pharmacology; Population; Production; RAPGEF2 gene; Role; Rupture; S100 Calcium Binding Protein; S100A4 gene; Signal Transduction; Signaling Molecule; Site; Tendon Injuries; Tendon structure; Testing; Tissues; Trifluoperazine; Type 2 diabetic; Up-Regulation; antagonist; diabetic; diet-induced obesity; extracellular; healing; impaired driving performance; improved; injury and repair; macrophage; mechanical properties; mouse model; new therapeutic target; non-diabetic; prevent; receptor; receptor binding; receptor for advanced glycation endproducts; regenerative; repaired; response; restoration; small molecule; sound; therapeutic target; translational applications

Effective surgical repair of tendon injuries is limited due to a propensity for scar tissue mediated healing rather than regeneration of native tendon structure. This fibrotic scar tissue results in impaired tendon function due to extracellular matrix (ECM) disorganization and inferior mechanical properties, relative to healthy tendon. Type II Diabetes Mellitus (T2DM) dramatically exacerbates this healing paradigm resulting in a more profound loss of tendon function, and increased incidence of re-rupture. Our understanding of the mechanisms that govern increased fibrotic healing in diabetic tendon remains limited, and this gap in knowledge has resulted in a paucity of therapeutic targets to improve clinical outcomes. Our previous studies have utilized a murine model of diet-induced obesity and T2DM that results in increased scar-formation and inferior mechanical properties during tendon healing, however, the mechanisms driving these impairments in healing are unknown. Our preliminary data identify extracellular S100a4 (S100 calcium binding protein 4A) signaling as a key driver of fibrotic tendon healing in non-diabetic animals. S100a4-haploinsufficiency decreases scarring and accelerates improvements in mechanical properties, relative to WT, while S100a4-cell depletion also decreases scar tissue formation, but decreases mechanical properties, suggesting that S100a4-producing cells are required for mechanically sufficient tendon healing. Given that S100a4 and RAGE expression are dramatically increased in diabetic tendon repairs we propose that fibrotic healing occurs to a greater degree in diabetic tendons than non-diabetic due to elevated S100a4-RAGE signaling. Thus, in the present study we will use a murine model diet induced obesity and T2DM in conjunction with acute tendon injury and repair to test the central hypothesis that inhibition of the increased and sustained activation of pro-fibrotic S100a4-RAGE activity in diabetic tendons will promote mechanically superior, regenerative tendon healing. We will test this hypothesis through the following specific aims: Aim 1: Identify the S100a4-producing cell population during tendon healing and the specific effects of S100a4 conditional deletion on scar tissue formation and acquisition of mechanical strength after injury in diabetic tendons. Aim 2: Define the effects of global and macrophage-specific deletion of RAGE on scar-mediated diabetic tendon healing as a mechanism of reduced S100a4 signaling. Aim 3: Assess the efficacy of small molecule inhibition of S100a4 and RAGE to improve diabetic tendon healing.

肌腱损伤的有效手术修复是有限的，这是由于疤痕组织介导愈合的倾向，而不是 比原生肌腱结构的再生更重要。这种纤维化瘢痕组织由于以下原因导致肌腱功能受损： 细胞外基质（ECM）解体和较差的机械性能，相对于健康的肌腱。类型 II型糖尿病（T2 DM）显著加剧了这种愈合模式，导致更严重的损失 肌腱功能，并增加再断裂的发生率。我们对控制人类行为的机制的理解 糖尿病肌腱纤维化愈合的增加仍然有限，这种知识上的差距导致了 缺乏改善临床结果的治疗靶点。我们以前的研究利用了小鼠模型 导致瘢痕形成增加和机械性能较差的饮食诱导的肥胖和T2 DM 然而，在肌腱愈合过程中，驱动这些愈合损伤的机制尚不清楚。我们 初步数据确定细胞外S100 a4（S100钙结合蛋白4A）信号传导是 非糖尿病动物的纤维化肌腱愈合。S100 a4-单倍不足减少瘢痕形成并加速 相对于WT，机械性能的改善，而S100 a4细胞去除也减少了瘢痕组织 形成，但降低机械性能，表明S100 a4产生细胞是必需的， 机械性肌腱愈合。考虑到S100 a4和p53的表达显著增加， 糖尿病肌腱修复我们认为糖尿病肌腱的纤维化愈合程度高于 由于S100 a4-β信号传导升高而非糖尿病。因此，在本研究中，我们将使用小鼠模型 饮食诱导的肥胖和T2 DM与急性肌腱损伤和修复相关，以检验中心假设 抑制糖尿病患者促纤维化S100 a4-β 1活性的增加和持续活化， 肌腱将促进机械性的上级再生肌腱愈合。我们将通过以下方式来验证这一假设： 目的1：鉴定肌腱愈合过程中产生S100 a4的细胞群， S100 a4条件性缺失对瘢痕组织形成和机械强度获得的特异性影响 在糖尿病肌腱损伤后。目的2：确定整体和巨噬细胞特异性缺失的影响 作为减少S100 a4信号传导的机制，对瘢痕介导的糖尿病肌腱愈合的影响。目标3：评估 小分子抑制S100 a4和S100 a4对改善糖尿病肌腱愈合功效。