Modulation of Angiogenesis by Regulated Dimerization

通过调节二聚化调节血管生成

• 批准号: 6321189
• 负责人: KEVIN M PUMIGLIA
• 金额: $ 15.5万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6321189
• 关键词: Adenoviridae; FK506; angiogenesis; angiogenesis factor; autocrine; binding proteins; cell migration; chimeric proteins; dimer; drug receptors; growth factor receptors; human tissue; laboratory rat; mitogen activated protein kinase; mitogens; recombinant virus; vascular endothelial growth factors; vascular endothelium

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.

描述（申请人的摘要）：氧气和氧气的不间断输送， 营养素是人体生长、维持和生存所必需的 组织中为了应对损伤、炎症或缺氧应激， 通常以血管生成生长因子的上调应答， 反过来刺激血管生成，新血管的生长。中断 组织损伤和这种代偿性新血管形成之间的平衡是 与心肌梗死相关的病理结果直接相关 梗塞、糖尿病性血管疾病、血管闭塞性疾病和衰老。 直接血运重建疗法是治疗糖尿病的一种新兴疗法。 灌注不充分的组织，主要是通过增加正常的 血管生成反应这已经通过使用血管生成生长的递送来完成 例如VEOF等因素直接作用于原位组织，或 循环内皮祖细胞（EPC），已扩增， 体内，并回家组织缺氧的网站，并提高自然 发生血管生成反应。这份R21提案旨在探索 并开发了一种替代方法：VEGF受体的递送， 已经被修改以响应生物活性的小分子药物， 二聚化的化学诱导剂（CID），并以一种方式激活受体 独立于VEGF。该系统的开发将使药理学 调节定向血管生成反应，并结合EPC模式， 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，发展 该系统提供了一个关键的实验平台， VEGF受体的结构-功能研究， 在细胞和分子水平上理解血管生成。