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。这一过程中的改变可导致血管异常和组织发育受损。 尽管关于促进肺血管系统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却一无所知。 因此，本提案的总体目标是首次在分子水平上确定一种推定的肺血管生长负调节剂的作用。我选择专注于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，并且我现在有初步数据表明它可能在发育中的小鼠肺内负调节血管生成中发挥关键作用。 我推测EMAP II是肺生理发育和新生血管形成的重要负调节因子。本研究的具体目的是：1）明确EMAP II在小鼠胚胎肺中的时空表达; 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抑制血管内皮细胞生长的分子基础。通过进一步教育在胚胎学，发育生物学，细胞周期控制和基因调控/表达我的研究生涯的发展是这个项目的目标。 这些与教育课程结合的拟议研究将确定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影响。 基于这些信息，缺血再灌注损伤，慢性肺损伤和肺移植后的肺再生的临床治疗的新方法可能会被确定，并进一步扩展我的研究生涯。

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.