ROLE OF A NEGATIVE MODULATOR OF NEOVASCULARIZATION

新血管化负调节剂的作用

• 批准号: 6638084
• 负责人: Margaret A Schwarz
• 金额: $ 10.29万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6638084
• 关键词: SCID mouse; angiogenesis; angiogenesis factor; angiogenesis inhibitors; cell cycle; cell growth regulation; cell proliferation; developmental genetics; flow cytometry; gene expression; immunocytochemistry; in situ hybridization; laboratory mouse; lung; monocyte; nonsurgical revascularization; polymerase chain reaction; vascular endothelial growth factors; western blottings

Neovascularization is a key regulatory process in fetal growth and development, providing nutrients and oxygen to tissues. Alterations within this process can lead to vascular abnormalities and impaired tissue development. Although a great deal is known regarding the interaction of factors promoting growth and development of the pulmonary vasculature, nothing is known regarding the molecular mechanisms that may counteract these stimuli. Accordingly the overall goals of this proposal are to determine, at a molecular level for the first time, the role of one putative negative modulator of lung vascular growth. I chose to focus on Endothelial monocyte activating polypeptide (EMAP) II as a candidate negative modulator because we recently identified a novel role for this cytokine as an anti-angiogenic factor in tumor vascular development and I now have preliminary data indicating that it may play a key role in negatively modulating angiogenesis within the developing mouse lung. I hypothesize that EMAP II is an important negative-regulator in the physiologic development and neovascularization of the lung. The specific aims of this project are: 1) To define the temporo-spatial expression of EMAP II in the embryonic mouse lung, 2) To determine the mechanism by which EMAP II inhibits lung vascular development, and 3) To determine the molecular basis by which EMAP II, an anti-angiogenic factor, inhibits vascular endothelial cell growth by analyzing the effect of exogenous EMAP II on cell proliferation, and cell cycle events. Development of my research career through further education in embryology, developmental biology, cell cycle control, and gene regulation/expression are the goals of this project. These proposed studies in conjunction with the education courses will determine whether EMAP II is an important negative regulator in lung development and neovascularization and will determine the effect of abrogation and overexpression. Based on this information, novel approaches to the clinical treatment of lung regeneration after ischemia-reperfusion injury, chronic lung damage and lung transplantation may be identified and further expansion of my research career.

新生血管形成是胎儿生长和发育的关键调节过程，为组织提供营养和氧气。这一过程的改变可能导致血管异常和组织发育受损。 尽管人们对促进肺血管系统生长和发育的因素的相互作用了解很多，但对于可能抵消这些刺激的分子机制却一无所知。 因此，该提案的总体目标是首次在分子水平上确定一种假定的肺血管生长负调节剂的作用。我选择关注内皮单核细胞激活多肽 (EMAP) II 作为候选负调节剂，因为我们最近发现了这种细胞因子作为肿瘤血管发育中的抗血管生成因子的新作用，而且我现在有初步数据表明它可能在负调节小鼠肺部发育中的血管生成中发挥关键作用。 我假设 EMAP II 是肺部生理发育和新血管形成的重要负调节因子。该项目的具体目标是：1）确定EMAP II在胚胎小鼠肺中的时空表达，2）确定EMAP II抑制肺血管发育的机制，3）通过分析外源性EMAP II对细胞增殖和细胞周期事件的影响，确定EMAP II（一种抗血管生成因子）抑制血管内皮细胞生长的分子基础。该项目的目标是通过胚胎学、发育生物学、细胞周期控制和基因调控/表达方面的进一步教育来发展我的研究生涯。 这些拟议的研究与教育课程相结合将确定 EMAP II 是否是肺发育和新血管形成的重要负调节因子，并将确定废除和过度表达的效果。 基于这些信息，可以确定缺血再灌注损伤、慢性肺损伤和肺移植后肺再生临床治疗的新方法，并进一步扩展我的研究生涯。