Molecular mechanisms of Foxc-mediated angiogenesis

血管的形成依赖于对紧密相连的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，对这些过程的转录控制仍然不完全清楚。长期目标 我们实验室的主要任务是阐明调节血管形成的基本机制，并 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FOXC2是Fox(Forkhead Box)转录因子家族中密切相关的成员，并具有 在血管发育和疾病中的关键作用。人类FOXC1基因拷贝数的突变或变化 与常染色体显性AXENFELD-Rieger综合征(ARS)有关，ARS的特征是 眼段缺陷和脑小血管疾病，而FOXC2基因失活突变是原因 常染色体显性淋巴水肿-二叉症综合征，包括迟发等症状 淋巴水肿和睫毛过长(双眼症)。我们已经完成了初步实验，表明(1) 突变与丝状足的形成和血管生成前沿的增殖减少有关， 毛细血管丛血管密度和分支缺陷，血管构型受损；以及(2) 这些血管生成缺陷伴随着哺乳动物靶基因活性的显著下降。 雷帕霉素(MTOR)和CD98的表达，CD98输入必需的氨基酸，如亮氨酸，而 出口非必需氨基酸谷氨酰胺。因此，我们的中心假设是FOXC转录 因子通过调节氨基途径参与生理性和病理性血管生成 酸转运、EC代谢和mTOR信号转导。在强劲的初步数据的指引下，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)确定Foxc1和Foxc1 FOXC2协同参与生理性和病理性血管生成。总而言之，这些结果 从本提案中描述的实验中产生的数据将提供有关形成的关键信息 关于血管；因此，因为血管缺陷是心血管疾病的主要原因之一 和疾病，我们的发现可能会确定新的靶点和治疗策略来改善血管 受影响患者的形成和功能。

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.