application) Integrins are an important family of cell surface receptors that bind to insoluble ECM proteins and transduce cell signals involved in fundamental cellular functions. Some integrins also act as receptors for soluble ligands, such as fibrinogen and fragments of matrix proteins. Fragmented ECM proteins are known to be generated during tissue injury. The investigators hypothesize that these fragments act as unique biologically active signals capable of altering microvascular functions through their interactions. They propose that these ECM-derived signals may play an important role in the vascular response to injury. The preliminary studies show that isolated arterioles dilate in response to peptide fragments containing the RGD but not the RGE sequence. This dilatory response does not require endothelium and appears to be mediated through RGD binding to avb3. Similar dilatation was observed in response to proteolytic fragments of denatured collagen known to be generated during tissue injury, suggesting that collagen may act as an in vivo source of these ligands. Collagens, which are the most abundant matrix proteins, contain multiple RGD sequences per molecule. Proteolysis could theoretically liberate soluble RGD or non-RGD peptides which could then interact with vascular wall integrins. The investigators hypothesize that the ECM can act as a source of unique RGD or non-RGD-containing peptides capable of regulating vasomotor function.
The specific aims are: 1) Characterize the vasomotor response of isolated arterioles and intact microvascular preparations to known integrin binding peptides and collagen fragments; 2) Isolate and identify the active peptides that are generated from proteolytically cleaved denatured type I collagen; and 3) Identify intracellular signaling pathways responsible for vasoactivity. The ability of integrin binding peptides to initiate changes in cell function and elicit physiological responses is of potential therapeutic interest because integrin ligands may be useful in the manipulation of vascular function and the response to injury.
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