Modulation of Angiogenesis by Regulated Dimerization

描述(申请人摘要)：不间断地输送氧气和 营养素对人体的生长、维持和生存至关重要。 纸巾。作为对损伤、炎症或低氧压力的反应，身体 典型的反应是上调血管生成生长因子，这种生长因子在 反过来刺激血管生成，新血管的生长。中途中断 组织损伤和这种代偿性新生血管之间的平衡是 与心肌梗死相关的病理结果直接相关 脑梗塞、糖尿病血管疾病、血管闭塞疾病和衰老。 直接血运重建治疗是一种新兴的治疗模式。 血流不充分的组织，主要是由于正常组织的增大 血管生成反应。这是通过输送血管新生生长来实现的。 因素，如VEOF直接到组织原位，或交付 循环内皮祖细胞(EPC)，已扩增 活体内，哪些部位的组织缺氧和增强自然 发生血管生成反应。这份R21提案针对的是勘探 并开发了一种替代方法：传递一种可 已经被改造成对一种生物活性的小分子药物产生反应，这种药物是一种 化学二聚化诱导剂(CID)，并以一种方式激活受体 不依赖于血管内皮生长因子。这一系统的开发将使药理学 调节定向血管生成反应，并与EPC模式相结合 治疗，将有能力提供精致的时间和空间 控制诱导的治疗性血管生成。此外，还包括 该系统为测试系统的性能提供了关键的实验平台 血管内皮生长因子受体的结构-功能研究，这是 在细胞和分子水平上了解血管生成。

DESCRIPTION (Applicant's abstract): The uninterrupted delivery of oxygen and nutrients is essential for the growth, maintenance and survival of body tissues. In response to injury, inflammation, or hypoxic stress, the body typically responds with an upregulation of angiogenic growth factors, which in turn stimulate angiogenesis, the growth of new blood vessels. Disruptions in the balance between tissue injury and this compensatory neovascularization is directly related to the pathological outcomes associated with myocardial infarction, diabetic vascular disease, vascular occlusive disease, and aging. Direct revascularization therapy is an emerging mode of therapy for treating inadequately perfused tissues, essentially by augmentation of the normal angiogenic response. This has been done using the delivery of angiogenic growth factors such as VEOF directly to the tissue in situ, or the delivery of circulating endothelial progenitor cells (EPC), which have been expanded ex vivo, and which home to the sites of tissue hypoxia and enhance the naturally occurring angiogenic response. This R21 proposal is directed at the exploration and development of an alternate approach: the delivery of a VEGF-receptor that has been modified to respond to a bioactive, small molecule drug, which is a chemical inducer of dimerization (CID), and activates the receptor in a manner independent of VEGF. The development of this system will allow pharmacological regulation of a directed angiogenic response, and combined with EPC modes of therapy, would have the capacity to provide exquisite temporal and spatial control over induced therapeutic angiogenesis. In addition, the development of this system provides a critical experimental platform for the performance of structure-function studies of the VEGF receptors, a prerequisite for understanding angiogenesis at the cell and molecular level.