E2F-mediated Control of Vascular Growth and Remodeling

描述(申请人提供)：旁路移植和动脉血管成形术后血管平滑肌细胞(VSMC)的增殖和迁移可导致移植物失败和再狭窄。这一病理过程被称为内膜增生。限制移植血管或血管成形术后的血管内膜增生是一个至关重要的治疗目标。最近的一些研究试图通过将细胞周期蛋白抑制剂输送到旁路移植物或血管成形术部位来限制VSMC的增殖和内膜增生。由Dzau和他的同事开发的最有希望的方法之一，针对E2F转录因子家族进行抑制。许多研究表明，视网膜母细胞瘤肿瘤抑制蛋白(Rb)和其他Rb家族成员的生长抑制作用依赖于它们调节E2F转录因子家族的能力。根据序列同源性和功能特性，E2F转录因子家族可以分为两个亚类。第一个亚类包括E2F1、E2F2和E2F3，是诱导静止细胞增殖的转录激活剂。第二个亚类E2F4、E2F5和E2F6在抑制E2F反应基因和细胞增殖中起重要作用。与E2F4的抑制作用一致，我们最近确定缺乏E2F4的小鼠在动脉损伤后发生加速的内膜增生。我们的总体假设是，抑制单个(或部分)E2F可以减少或增强血管损伤或移植后的内膜增生，详细了解各种E2F如何在内膜增生过程中控制血管平滑肌细胞增殖将有助于开发出更特异和更有效的这一病理过程的抑制物。我们的具体目标是1。)为了利用转基因小鼠确定促进内膜增生和抑制此病理过程的E2F家族成员，2)利用转基因小鼠探讨多个E2F活性的扰动如何影响内膜增生和再狭窄；3)开发专门针对那些促进内膜增生的E2F家族成员的适配子，并评估这些适配子在静脉移植失败和动脉再狭窄动物模型中限制内膜增殖的能力。因此，这些实验将描绘出应针对E2F家族成员(S)的抑制，以减少人类再狭窄和移植静脉失败的发生，并产生可能对接受旁路手术或血管成形术的个体进行有效治疗的新型治疗化合物。

DESCRIPTION (provided by applicant): Vascular smooth muscle cell (VSMC) proliferation and migration following by-pass grafting and arterial angioplasty can lead to graft failure and restenosis. This pathological process is known as intimal hyperplasia. Limiting intimal hyperplasia in grafted vessels or a vessel following angioplasty is a critically important therapeutic target. A number of recent studies have attempted to limit VSMC proliferation and intimal hyperplasia by delivering inhibitors of cell cycle proteins to by-pass grafts or sites of angioplasty. One of the most promising approaches, developed by Dzau and colleagues, targets the E2F family of transcription factors for inhibition. A number of studies have shown that the growth suppression action of the retinoblastoma tumor suppressor protein (Rb) and other Rb family members is dependent on their ability to regulate the E2F family of transcription factors. It has also become increasingly clear that the E2F family of transcription factors can be divided into 2 subclasses based upon sequence homology and functional properties. The first subclass, containing E2F1, E2F2 and E2F3, are transcriptional activators that induce quiescent cells to proliferate. The second subclass, E2F4, E2F5 and E2F6 are important in the repression of E2F responsive genes and cell proliferation. Consistent with the repressor role of E2F4, we have recently determined that mice lacking E2F4 undergo accelerated intimal hyperplasia following arterial injury. Our Overall Hypothesis is that inhibition of individual (or subsets of the) E2Fs can reduce or enhance intimal hyperplasia following vessel damage or grafting and that a detailed understanding of how the various E2Fs control vascular smooth muscle cell proliferation during intimal hyperplasia will facilitate the development of more specific and potent inhibitors of this pathological process. Our Specific Aims are 1.) To determine the E2F family members that promote intimal hyperplasia and those that repress this pathological process using genetically modified mice, 2) To explore how perturbations in multiple E2F activities affect intimal hyperplasia and restenosis using genetically modified mice and 3) To develop aptamers that specifically target those E2F family that promote intimal hyperplasia and to evaluate the ability of these aptamers to limit intimal hyperplasia in animal models of vein graft failure and arterial restenosis Thus these experiments will delineate the E2F family member(s) that should be targeted for inhibition to reduce the occurrence of restenosis and vein-graft failure in humans and yield novel therapeutic compounds that may be useful in the treatment of individuals undergoing by-pass surgery or angioplasty.