Growth and Function of Cultured Gastrointestinal Muscle

描述（由申请人提供）：这项工作的总体假设是IGF-I系统，？V？3整合素和？V？3整合素结合配体，玻连蛋白和纤连蛋白，调节平滑肌增生，过量的胶原蛋白的生产和纤维化的肠是中央狭窄形成克罗恩病，选择性IGF-I和？V？3抑制剂可用于减少肌肉增生、纤维化和狭窄形成。我们的研究在目前的资助期间已经确定的机制，内源性IGF-I，IGFBP-5，IGFBP-3和？小维3整联蛋白共同调节正常肠肌中的平滑肌生长和胶原II产生，以及克罗恩病和TNBS诱导的结肠炎小鼠中的过度肌肉生长、胶原II产生和纤维化。占领？小维3整合素通过其配体玻连蛋白和纤连蛋白调节IGF-I刺激的强度和持续时间、IGF-I受体活化和效应。我们最近的工作和初步的结果表明，在狭窄的克罗恩病，平滑肌与TNBS诱导的结肠炎小鼠增加内源性？V？3整合素配体。由此产生的激活？小维3整联蛋白与上调的内源性IGF-I和IGF结合蛋白一起是平滑肌细胞增生、增加的胶原II产生和导致的纤维化的中心介质。肌肉增生，胶原蛋白II生成，？V？3整合素依赖性效应和纤维化可以通过药物阻断？小维3整合素活化或IGF-I受体活化。第一个具体目标是确定调节IGF-I和IGFBP-5表达增加的机制及其在狭窄性克罗恩病和慢性TNBS诱导的结肠炎中肌肉增生、胶原蛋白产生和纤维化发展中的作用。第二个具体目标是表征机制调节？小维3整合素结合的玻连蛋白和纤连蛋白的表达及其功能V？3整合素活化和肌肉增生、胶原蛋白产生和纤维化在狭窄性克罗恩病和慢性TNBS诱导的结肠炎中的发展。第三个具体目标是表征的机制调节？V和？3整合素亚基的表达及作用？V？3在狭窄性克罗恩病和慢性TNBS诱导的结肠炎中肌肉增生、胶原蛋白产生和纤维化中的整合素活化。他们的完成将促进我们的理解独特的病理生理学的肠平滑肌增生，胶原蛋白的生产，纤维化和狭窄的形成在发炎的肠道和确定潜在的治疗策略，通过？V？3整合素和IGF-I受体抑制，以减少狭窄性克罗恩病患者的狭窄形成。 公共卫生相关性：该提案的目的是表征内源性因素和介导克罗恩病中平滑肌增生、胶原蛋白产生和纤维化导致狭窄形成的相互依赖的信号通路。该项目涉及的分子机制分析？V？3整合素，及其配体调节IGF-I依赖性和IGF结合蛋白依赖性肌肉增生，胶原蛋白的产生和纤维化的起始和进展的狭窄形成在炎症过程中，并确定是否适合？V？3和IGF-I抑制剂以减少克罗恩病中的纤维化和狭窄形成。

DESCRIPTION (provided by applicant): The overall hypotheses underlying this work are that IGF-I system, ?V?3 integrin and the ?V?3 integrin-binding ligands, vitronectin and fibronectin, regulate the smooth muscle hyperplasia, excess collagen production and fibrosis in the intestine that is central to stricture formation in Crohn's disease, and that selective IGF-I and ?V?3 inhibitors can be used to diminish muscle hyperplasia, fibrosis and stricture formation. Our studies during the current funding period have identified the mechanisms by which endogenous IGF-I, IGFBP-5, IGFBP-3 and ?V?3 integrin act jointly to regulate smooth muscle growth and collagen II production in normal intestinal muscle and excess muscle growth, collagen II production and fibrosis in Crohn's disease and in TNBS-induced colitis in mice. Occupancy of ?V?3 integrin by its ligands, vitronectin and fibronectin, regulates the intensity and duration of IGF-I-stimulated, IGF-I receptor activation and effects. Our recent work and preliminary results show that, like smooth muscle in stricturing Crohn's disease, smooth muscle of mice with TNBS-induced colitis have increased endogenous ?V?3 integrin ligands. The resulting activation of ?V?3 integrin jointly with upregulated endogenous IGF-I and IGF binding proteins are central mediators of smooth muscle cell hyperplasia, increased collagen II production and resulting fibrosis. Muscle hyperplasia, collagen II production, ?V?3 integrin-dependent effects and fibrosis can be decreased by pharmacologic blockade of ?V?3 integrin activation or of IGF-I receptor activation. The first specific aim is to identify the mechanisms regulating increased IGF-I and IGFBP-5 expression and their roles in the development of muscle hyperplasia, collagen production and fibrosis in stricturing Crohn's disease and chronic TNBS-induced colitis. The second specific aim is to characterize the mechanisms regulating ?V?3 integrin binding vitronectin and fibronectin expression and their function in ?V?3 integrin activation and development of muscle hyperplasia, collagen production and fibrosis in stricturing Crohn's disease and chronic TNBS- induced colitis. The third specific aim is to characterize the mechanisms regulating ?V and ?3 integrin subunit expression and the role of ?V?3 integrin activation in muscle hyperplasia, collagen production and fibrosis in stricturing Crohn's disease and chronic TNBS-induced colitis. Their completion will advance our understanding of the unique pathophysiology of intestinal smooth muscle hyperplasia, collagen production, fibrosis and stricture formation in the inflamed intestine and identify potential therapeutic strategies, via ?V?3 integrin and IGF-I receptor inhibition, to decrease stricture formation in patients with stricturing Crohn's disease. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to characterize the endogenous factors and the interdependent signaling pathways that mediate smooth muscle hyperplasia, collagen production and fibrosis leading to stricture formation in Crohn's disease. The project involves analysis of the molecular mechanisms by which the ?V?3 integrin, and its ligands regulate IGF-I-dependent and IGF binding protein-dependent muscle hyperplasia, collagen production and fibrosis in the initiation and progression of stricture formation during inflammation and to determine the suitability of ?V?3 and IGF-I inhibitors to diminish fibrosis and stricture formation in Crohn's disease.