PKC-Delta in Intimal Hyperplasia after Vascular Bypass

血管搭桥术后内膜增生中的 PKC-Delta

• 批准号: 6960764
• 负责人: K CRAIG Kent
• 金额: $ 42万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-19 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6960764
• 关键词: apoptosis; blood vessel disorder; cardiovascular pharmacology; cardiovascular surgery; cell differentiation; cell migration; cell proliferation; chemoprevention; disease /disorder model; disease /disorder prevention /control; enzyme activity; enzyme induction /repression; enzyme mechanism; genetically modified animals; immunopharmacology; immunosuppressive; intraluminal angioplasty; laboratory mouse; laboratory rat; medical complication; protein kinase C; protein structure function; sirolimus; vascular smooth muscle

DESCRIPTION (provided by applicant): Intimal hyperplasia (IH), a disease process that accounts for tremendous morbidity and mortality in patients previously treated with angioplasty or vascular reconstruction, is typified by dedifferentiated vascular smooth muscle cells (VSMC) that proliferate, migrate, and are resistant to apoptosis. In preliminary studies, we found that a subtype of protein kinase C, PKC delta (PKCd), profoundly regulates VSMCs in vitro. Specifically, PKCd inhibits SMC proliferation and migration and stimulates SMC apoptosis and differentiation. Moreover, we found that rapamycin, which inhibits restenosis when applied via coronary stents, increases PKCd in cultured VSMCs, suggesting PKCd may be the signal through which rapamycin exerts its profound inhibitory effect. Based on the foregoing, we propose that the potent effects of PKCd on VSMCs might allow this molecule, or a modification, to be used as a specific preventative therapy. We will begin with studies to define the pathways through which PKCd affects VSMC proliferation, apoptosis, and migration and confirm our preliminary data showing downstream regulation through ERK1, p38 and p53. In specific aim II, we will dissect the PKCd molecule to understand the regulatory mechanism that governs its effects in VSMCs. Specifically; we will evaluate the ability of the catalytic or regulatory domain, as well as phosphorylation of specific tyrosine residues, to regulate PKCd's control over proliferation, migration and apoptosis. In specific aim III, we will test the role of PKCd through three distinct molecular manipulations in rat and mouse arterial injury models. Finally, in aim IV, we will test the hypothesis, both in vivo and in vitro, that rapamycin affects SMC behavior and IH through induction of PKCd. We anticipate that these studies will further our knowledge of the mechanisms and pathways that contribute to the formation of IH. Moreover, we are encouraged by the profound effect that PKCd has on the SMC dysfunction that accompanies IH and postulate that upregulation of this molecule will be a potential strategy for the prevention of this devastating condition.

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