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aV¿3整合素及其配体，纤维连接蛋白和玻璃体连接蛋白，调节正常组织中IGF-I刺激的生长，并且它们的增加与炎症中的IGF-I和IGFBP5一起在启动平滑肌增生中至关重要。人肠道平滑肌的生长在一定程度上是通过内源性生长肽的相互作用来调节的。我们在之前的资助期内的研究已经确定了两种生长因子，IGF-I和IGFBP-5，它们协同调节人类肠道平滑肌的生长。内源性IGF-I通过IGF-I受体刺激细胞增殖，抑制细胞凋亡。IGFBP-5促进IGF-I受体被IGF-I激活。IGFBP-5也通过激活自身的IGFBP-5受体刺激肠平滑肌的生长。igf - 1和IGFBP-5之间独特的相互作用，刺激生长和彼此的分泌，加强了它们对生长的个体作用，并可能导致肠道炎症引起的肌肉增生。初步结果表明，IGF-I受体激活、IGF-I刺激的肌肉生长和IGFBP-5分泌受aV¿3整合素调控，并可通过aV¿3整合素配体纤维连接蛋白增强。我们发现纤维连接蛋白和玻璃体连接蛋白在发炎的肠道肌肉中上调。因此，本提案的目的是确定aV¿3整合素及其配体，纤维连接蛋白和玻璃体连接蛋白调节IGF- i受体活性的机制，以及这些aV¿3配体以及IGF- i和IGF结合蛋白-5 （IGFBP-5）在炎症期间启动肌肉增生中的表达增加的意义。

DESCRIPTION (provided by applicant): The overall hypotheses underlying this work are that aV¿3 integrin and its ligands, fibronectin and vitronectin, regulate IGF-I stimulated growth in normal tissue, and that their increased production together with IGF-I and IGFBP5 in inflammation are crucial in initiating smooth muscle hyperplasia. Growth of human intestinal smooth muscle is regulated in part through the interplay of endogenous growth peptides. Our studies during the previous funding period have identified two growth factors, IGF-I and IGFBP-5, which act in concert to regulate human intestinal smooth muscle growth. Endogenous IGF-I stimulates proliferation and inhibits apoptosis via the IGF-I receptor. IGFBP-5 facilitates activation of the IGF-I receptor by IGF-I. IGFBP-5 also stimulates growth of intestinal smooth muscle by activating its own IGFBP- 5 receptor. A unique interaction between IGF-I and IGFBP-5 to stimulate growth and each others' secretion reinforces their individual effects on growth and may contribute to the muscle hyperplasia resulting from intestinal inflammation. Preliminary results showed that IGF-I receptor activation, muscle growth and IGFBP-5 secretion stimulated by IGF-I were regulated by the aV¿3 integrin and could be augmented by the aV¿3 integrin ligand, fibronectin. We showed that fibronectin and vitronectin are upregulated in inflamed intestinal muscle. The objective of this proposal therefore is to determine the mechanisms by which the aV¿3 integrin and its ligands, fibronectin and vitronectin, regulate IGF-I receptor activity and the significance of increased expression of these aV¿3 ligands as well as IGF-I and IGF binding protein-5 (IGFBP-5) in initiating muscle hyperplasia during inflammation. The first specific aim is to characterize the regulation of IGF-I-stimulated IGF-I receptor phosphorylation by aV¿3 integrin signaling pathways in intestinal smooth muscle cells. The second aim is to examine the regulation of IGF-I-stimulated muscle cell proliferation, upregulation of IGFBP-5; and inhibition of apoptosis by endogenous aV¿3 integrin ligands. The third specific aim is to identify the role of upregulated aV¿3 integrin ligands in initiating altered IGF-I-stimulated growth in inflamed intestinal smooth muscle. Each specific aim is supported by substantial preliminary studies. Their completion should advance our understanding of the regulation of smooth muscle growth in normal muscle and mechanisms crucial to initiating smooth muscle hyperplasia in the setting of inflammation.