Molecular mechanisms of Foxc-mediated angiogenesis

血管系统的形成依赖于分子网络的精确控制， 受促血管生成生长因子和参与内皮细胞（EC）代谢的分子调节。 然而，这些过程的转录控制仍然不完全清楚。远景目标 我们实验室的目的是阐明调节血管形成的基本机制， 了解这些机制的破坏如何导致病理环境中的血管缺陷。FOXC1 和FOXC 2是FOX（叉头盒）转录因子家族的密切相关的成员， 在血管发育和疾病中起关键作用。人类FOXC 1拷贝数的突变或变化 与常染色体显性Axenand-Rieger综合征（ARS）相关，其特征是前 眼段缺陷和脑小血管疾病，而FOXC 2的失活突变负责 常染色体显性遗传性双列吸虫病综合征，其中包括症状，如迟发性 水肿和额外的睫毛（双睫）。我们已经完成了初步的实验，表明（1） 这些突变与丝状伪足形成和血管生成前沿增殖的下降有关， 毛细血管丛中血管密度和分支的缺陷，以及受损的血管图案;以及（2） 这些血管生成缺陷伴随着哺乳动物靶蛋白活性的显著下降， 雷帕霉素（mTOR）和CD 98的表达，其输入必需氨基酸如亮氨酸， 输出非必需氨基酸谷氨酰胺。因此，我们的中心假设是Foxc转录 参与生理和病理性血管生成的因子通过调节氨基 酸转运、EC代谢和mTOR信号传导。在强有力的初步数据的指导下，这一假设将是 通过追求两个具体目标进行测试：1）确定连接Foxc的分子和遗传网络 转录因子与血管生成和EC代谢; 2）定义Foxc 1和 Foxc 2协同参与生理和病理性血管生成。总之，结果 从本提案中描述的实验中产生的数据将提供有关地层的关键信息。 因此，由于血管缺陷是心血管疾病的主要原因之一， 和疾病，我们的研究结果可能会找到改善血管的新靶点和治疗策略 在患者中的形成和功能。

Formation of the blood vasculature depends on the precise control of molecular networks that are tightly regulated by proangiogenic growth factors and by molecules involved in endothelial cell (EC) metabolism. However, the transcriptional control of these processes remains incompletely understood. The long-term goal of our lab is to elucidate the fundamental mechanisms that regulate the formation of blood vessels and to understand how the disruption of these mechanisms leads to vascular defects in pathological settings. FOXC1 and FOXC2 are closely related members of the FOX (Forkhead box) transcription factor family and have critical roles in vascular development and disease. Mutations or changes in the copy number of human FOXC1 are associated with autosomal-dominant Axenfeld-Rieger syndrome (ARS), which is characterized by anterior eye segment defects and cerebral small vessel disease, while inactivating mutations of FOXC2 are responsible for autosomal-dominant lymphedema-distichiasis syndrome, which includes symptoms such as late-onset lymphedema and extra eyelashes (distichiasis). We have completed preliminary experiments suggesting (1) that the mutations are associated with declines in filopodia formation and proliferation at the angiogenic front, defects in vascular density and branching in the capillary plexus, and impaired vascular patterning; and (2) that these angiogenic defects are accompanied by significant declines in the activity of mammalian target of rapamycin (mTOR) and in the expression of CD98, which imports essential amino acids such as leucine while exporting the nonessential amino acid glutamine. Thus, our central hypothesis is that the Foxc transcription factors participate in physiological and pathological angiogenesis by regulating pathways involved in amino acid transport, EC metabolism, and mTOR signaling. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) identify the molecular and genetic networks that link the Foxc transcription factors with angiogenesis and EC metabolism; 2) Define the mechanisms by which Foxc1 and Foxc2 cooperatively participate in physiological and pathological angiogenesis. In summary, the results generated from the experiments described in this proposal will provide crucial information about the formation of blood vessels; thus, because vascular deficiencies are among the leading causes of cardiovascular disease and disorders, our findings are likely to identify new targets and therapeutic strategies for improving vascular formation and function in affected patients.