Growth and Function of Cultured Gastrointestinal Muscle

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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.