ROLE OF A NEGATIVE MODULATOR OF NEOVASCULARIZATION

新生血管是胎儿生长发育的关键调控过程，为组织提供营养和氧气。这一过程中的变化可能会导致血管异常和组织发育受损。虽然关于促进肺血管生长和发育的因素的相互作用已知很多，但关于可能抵消这些刺激的分子机制尚不清楚。因此，这项提案的总体目标是首次在分子水平上确定一个假定的肺血管生长负调控因子的作用。我选择将重点放在内皮单核细胞激活多肽(EMAP)II作为候选的负性调节剂，因为我们最近发现了这种细胞因子在肿瘤血管发育中的一个新的作用，我现在有初步的数据表明，它可能在发育中的小鼠肺内发挥负性调节血管生成的关键作用。我推测EMAP II在肺的生理发育和新生血管形成中是一个重要的负调节因子。本项目的具体目标是：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，确定抗血管生成因子EMAP II抑制血管内皮细胞生长的分子基础。通过在胚胎学、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事业是这个项目的目标。这些拟议的研究结合教育课程，将确定EMAP II是否在肺发育和新生血管中是一个重要的负面调节因素，并将确定废除和过度表达的效果。基于这一信息，可以确定临床治疗缺血再灌注损伤、慢性肺损伤和肺移植后肺再生的新方法，并进一步扩大我的研究生涯。

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.