Adenoviral vectors for delivery of angiogenic cytokines

用于递送血管生成细胞因子的腺病毒载体

• 批准号: 7093572
• 负责人: HAROLD FISHER DVORAK
• 金额: $ 41.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093572
• 关键词: Adenoviridae; angiogenesis; angiogenesis factor; athymic mouse; biological models; biotechnology; blood coagulation; cytokine; immunocytochemistry; ischemia; molecular pathology; pathologic arteriovenous shunt; protein isoforms; protein structure function; stem cells; tissue /cell culture; transfection /expression vector; vascular endothelial growth factors; vascular endothelium permeability

DESCRIPTION (provided by applicant): Tissue ischemia, whether of the heart or other organs, is a major clinical challenge. It has been widely hoped that angiogenic cytokines, such as vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) family members could grow new blood vessels to benefit such patients but success has not yet been realized. VEGF-A164, VEGF-A120 and PIGF generate a vascular response that is highly abnormal and that closely mimics that of pathological angiogenesis (e.g., healing myocardial infarcts). Several types of abnormal new blood vessels form: "mother" vessels and "daughter" vessels including glomeruloid bodies (GB), capillaries and vascular malformations and these are accompanied by vascular permeability, edema and clotting. However, the molecular mechanisms by which these vessels form is not yet understood. Also, to provide a useful blood supply, it is likely that more normal vessels are required. The first goal of this application is to elucidate the molecular mechanisms by which primary angiogenic cytokines such as VEGF-A164, VEGF-A120 and PIGF induce the abnormal new blood vessels that are typical of pathological angiogenesis. The second goal is to induce more normal vessels; this will be accomplished by supplementation of VEGF-A isomers with additional, secondary cytokines that have been suggested from studies of vasculogenesis and physiological angiogenesis, processes that lead to the formation of the normal vasculature. The studies we propose can provide a solid basis for translation to the bedside. Specific aims are as follows: Aim 1. Elucidate the mechanisms by which VEGF-A164, VEGF-A120 and PIGF induce mother vessels. Aim 2. Elucidate the mechanisms by which mother vessels evolve into daughter vessels. Aim 3. Generate normal blood vessels with mixtures of primary and secondary cytokines.

描述（由申请人提供）：组织缺血，无论是心脏还是其他器官，都是主要的临床挑战。人们普遍希望，血管生成细胞因子，例如血管渗透性因子/血管内皮生长因子（VPF/VEGF）家庭成员可以种植新的血管以使这种患者受益，但尚未实现成功。 VEGF-A164，VEGF-A120和PIGF产生一种高度异常的血管反应，并密切模仿病理血管生成的血管反应（例如，愈合心肌梗死）。几种异常的新血管形成：“母亲”血管和“女儿”血管，包括肾小球体（GB），毛细血管和血管畸形，并且伴随着血管通透性，水肿和凝结。但是，尚未了解这些血管形成的分子机制。同样，要提供有用的血液供应，可能需要更多的正常血管。该应用的第一个目标是阐明分子机制，通过这种机制，诸如VEGF-A164，VEGF-A120和PIGF等原发性血管生成细胞因子诱导了病理血管生成的典型新血管。第二个目标是诱导更多正常的血管。这将通过补充VEGF-A异构体和额外的继发性细胞因子来实现，这些因子是根据血管生成和生理血管生成的研究所建议的，这会导致形成正常的脉管系统。我们提出的研究可以为翻译到床边提供可靠的基础。具体目的如下：目标1。阐明VEGF-A164，VEGF-A120和PIGF诱导母船的机制。目标2。阐明母船演变成子船的机制。 AIM 3。产生正常的血管，含有原发性和次级细胞因子的混合物。