The extracellular protein elastin plays a significant role in the cardiovascular system by imparting an essential property of elasticity to aortic and arterial walls. A hallmark of the structural changes that occur in the development of atherosclerotic lesions include calcification and fragmentation of elastic fibers and the concomitant deposition of lipid material. Corrective angioplasty often results in restenosis with an accompanying increase in elastin synthesis concomitant with SMC proliferation. and increases in other matrix components. During the last funding period, we have found that IGF-I, a modulator associated with cardiovascular disease processes, increases elastin gene transcription. Further we have identified the cis and trans-acting factors involved in this response and shown that the transcription factors involved are ubiquitously expressed but appear to undergo specific interactions within the SMC to render them capable of modulating elastin transcription. In collaboration with Dr. Ravid and Dr. Sonenshein we have found that adenosine and B-myb modulate elastin promoter activity. In the present application we propose to build on our previous observations and determine the role and mechanisms underlying the IGF-1 regulation of elastin gene expression in cultured SMC. In addition we will pursue the identification of cAMP up-regulation of elastin transcription which is intimately tied into objectives proposed by Projects 1, 2 and 3.
Four specific aims are proposed to accomplish our objectives..
Aim 1 Characterize the DNA/protein interactions of Sp1/Sp3 with the elastin promoter in control and IGF-I treated SMC.
Aim 2 Examine the potential role of C/EBP family members in the transcriptional control of the elastin gene by IGF-I.
Aim 3 Characterize the role of the cyclin E in mediating the IGF-I regulation of elastin gene transcription.
Aim 4 Elucidate the cis element(s) and trans- acting factors involved in the up-regulation of elastin promoter activity by adenosine receptor mediated increases in cAMP. These studies should provide important insight into the response of elastin expression to events known to accompany aortic wall injury and further should define those factors responsible for these responses. The opportunity to couple our studies with those of Projects 1, 2 and 3 within the Program Project will allow us to related our findings to those of other matrix molecules (lysyl oxidase collagen) and their regulators (B-myb, cAMP) thereby providing a comprehensive and meaningful view of SMC response to aortic wall injury.
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