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) 是一种疾病过程，导致先前接受血管成形术或血管重建治疗的患者出现巨大的发病率和死亡率，其典型特征是增殖、迁移和抗凋亡的去分化血管平滑肌细胞 (VSMC)。在初步研究中，我们发现蛋白激酶 C 的一种亚型 PKC δ (PKCd) 在体外能够深刻调节 VSMC。具体来说，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可抑制再狭窄，可增加培养的 VSMC 中的 PKCd，表明 PKCd 可能是雷帕霉素发挥其深远抑制作用的信号。基于上述内容，我们提出 PKCd 对 VSMC 的有效作用可能允许该分子或修饰被用作特定的预防性治疗。我们将首先研究确定 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 ERK1、p38 和 p53 进行下游调节。在具体目标 II 中，我们将剖析 PKCd 分子，以了解控制其在 VSMC 中的作用的调节机制。具体来说;我们将评估催化或调节结构域以及特定酪氨酸残基磷酸化的能力，以调节 PKCd 对增殖、迁移和凋亡的控制。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，在目标 IV 中，我们将在体内和体外测试雷帕霉素通过诱导 PKCd 影响 SMC 行为和 IH 的假设。我们预计这些研究将进一步加深我们对 IH 形成机制和途径的了解。此外，我们对 PKCd 对伴随 IH 的 SMC 功能障碍产生的深远影响感到鼓舞，并假设该分子的上调将成为预防这种破坏性病症的潜在策略。