The overall hypotheses underlying this work are that V 3 integrin and its ligands, vitronectin and fibronectin, regulate IGF-I stimulated intestinal smooth muscle cell growth, and that their increased production along with that of IGF-I and IGF binding protein-3 and IGF binding protein-5 in the inflamed intestine, are crucial to initiating smooth muscle cell hyperplasia and contribute to stricture formation in Crohns disease. Growth of human intestinal smooth muscle is regulated in part through the interplay of endogenous growth peptides. Our studies during the current funding period have identified the mechanisms by which endogenous IGF-I and aVb3 integrin act jointly to regulate smooth muscle growth in normal intestinal muscle. Occupancy of aVb3 integrin by its ligands, vitronectin and fibronectin, regulates the intensity and duration of IGF-Istimulated, IGF-I receptor activation and smooth muscle cell growth by regulating the rate of translocation of tyrosine phosphatase SHP-2 from V 3 integrin to the activated IGF-I receptor and its subsequent dephosphorylation. Our recent work and preliminary results show that in smooth muscle cells isolated from stricturing Crohns disease, and from chronically inflamed smooth muscle cells from TNBS-induced colitis in wild-type, IGF-I(+/-), integrin 3(-/-), that upregulation of endogenous V 3 and integrin ligands, jointly with endogenous IGF-I are crucial to initiating smooth muscle cell hyperplasia. Preliminary results also show that the smooth muscle cell hyperplasia that occurs in stricturing Crohns disease and in TNBS-induced colitis can be inhibited by pharmacologic blockade of V 3 integrin activation or IGF-I receptor activation. The objectives of this proposal therefore are to determine the mechanisms regulating the increased expression of IGF-I, V 3 integrin, and its ligands vitronectin and fibronectin, their respective roles in the development of smooth muscle cell hyperplasia and stricture formation. The first specific aim is to identify the mechanisms regulating increased IGF-I and IGFBP-5 expression and their role in the development of muscle hyperplasia in Crohns disease and TNBS-induced colitis. The second specific aim is to characterize the mechanisms regulating fibronectin and vitronectin expression and their role in the development of IGF-I-stimulated muscle hyperplasia in Crohns disease and TNBS-induced colitis. The third specific aim is to identify the mechanisms regulating V and 3 integrin subunit expression and their role in the development of smooth muscle hyperplasia in Crohns disease and TNBS-induced colitis.
Each specific aim i s supported by substantial preliminary data. Their completion should advance our understanding of the regulation of smooth muscle hyperplasia and stricture formation in the inflamed intestine and identify potential therapeutic strategies to limit stricture formation in Crohns disease.
The objective of this proposal is to characterize the signal transduction pathways that mediate smooth muscle hyperplasia and hypertrophy during inflammation. The project involves analysis of the molecular mechanisms by which the aVb3 integrin, IGF-I and its ligands regulate IGF-I receptor activity and IGF-binding proteins in the initiation and maintenance of muscle growth during inflammation.
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