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: 7114355
• 负责人: K CRAIG Kent
• 金额: $ 41.01万
• 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/7114355
• 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.

描述（由申请人提供）： 内膜增生（IH）是一种导致既往接受血管成形术或血管重建术治疗的患者发病率和死亡率极高的疾病过程，其典型表现为去分化血管平滑肌细胞（VSMC）增殖、迁移和抗凋亡。在初步研究中，我们发现蛋白激酶C的一个亚型，PKC δ（PKCd），深刻地调节VSMCs在体外。具体地，PKCd抑制SMC增殖和迁移，并刺激SMC凋亡和分化。此外，我们发现，雷帕霉素，通过冠状动脉支架应用时，抑制再狭窄，增加PKCd在培养的VSMCs，这表明PKCd可能是雷帕霉素发挥其深刻的抑制作用的信号。基于上述，我们提出PKCd对VSMC的有效作用可能允许这种分子或修饰物用作特异性预防性治疗。我们将开始的研究，以确定PKCd影响VSMC增殖，凋亡和迁移的途径，并确认我们的初步数据显示，通过ERK 1，p38和p53的下游调控。在具体目标II中，我们将解剖PKCd分子，以了解其在VSMCs中作用的调控机制。具体而言;我们将评估催化或调节结构域以及特定酪氨酸残基的磷酸化调节PKCd对增殖、迁移和凋亡的控制的能力。在具体目标III中，我们将通过三种不同的分子操作在大鼠和小鼠动脉损伤模型中测试PKCd的作用。最后，在目的IV中，我们将在体内和体外检验雷帕霉素通过诱导PKCd影响SMC行为和IH的假设。我们预计，这些研究将进一步我们的知识的机制和途径，有助于形成IH。此外，PKCd对伴随IH的SMC功能障碍具有深远的影响，我们对此感到鼓舞，并假设上调该分子将是预防这种破坏性疾病的潜在策略。