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？积分素和V？3个整合素结合配体，玻璃体连接蛋白和纤维连接蛋白，调节平滑肌增生，过量胶原蛋白的产生和肠纤维化，这是克罗恩病狭窄形成的核心，并且选择性igf - 1和？3抑制剂可用于减少肌肉增生、纤维化和狭窄形成。我们在当前资助期内的研究已经确定了内源性igf - 1、IGFBP-5、IGFBP-3和IGFBP-5的机制。3整合素共同作用，调节小鼠克罗恩病和tnbs诱导结肠炎小鼠正常肠肌平滑肌生长和II型胶原生成，以及过量肠肌生长、II型胶原生成和纤维化。占用？V？3整合素通过其配体玻璃体连接蛋白和纤维连接蛋白调节IGF-I刺激的强度和持续时间、IGF-I受体的激活和作用。我们最近的工作和初步结果表明，与狭窄性克罗恩病的平滑肌一样，tnbs诱导结肠炎小鼠的平滑肌内源性？V？3个整合素配体。由此产生的？V？3整合素与上调的内源性IGF- i和IGF结合蛋白共同是平滑肌细胞增生、II型胶原生成增加和由此导致的纤维化的中心介质。肌肉增生，胶原蛋白生成，？3 .整合素依赖效应和纤维化可通过药物阻断？3整合素激活或igf - 1受体激活。第一个具体目的是确定IGF-I和IGFBP-5表达增加的调节机制及其在狭窄性克罗恩病和慢性tnbs诱导结肠炎中肌肉增生、胶原生成和纤维化的发展中的作用。第二个具体目标是描述调节？V？整合素结合玻璃体连接蛋白和纤维连接蛋白在V？3整合素激活与狭窄性克罗恩病和慢性TNBS诱导结肠炎中肌肉增生、胶原生成和纤维化的发展第三个具体目标是描述调节？V和？3整合素亚基表达与V？3整合素激活在狭窄性克罗恩病和慢性tnbs诱导结肠炎的肌肉增生、胶原生成和纤维化中的作用。这些研究的完成将促进我们对肠道平滑肌增生、胶原蛋白生成、纤维化和炎症肠道狭窄形成的独特病理生理学的理解，并确定潜在的治疗策略。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。

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.