Prox1 Phosphorylation in Lymphatic Development and Function

项目摘要 同源域转录因子PROX 1是诱导和维持细胞凋亡所必需的。 淋巴管内皮细胞特性。它不仅在最初的淋巴重编程中起重要作用， 扩张、成熟和维持，而且还指导腔和淋巴静脉瓣膜的形成。 尽管Prox 1的功能、结构和调控已被深入研究，但其机制仍不清楚。 如此众多的发育和环境信号被有效地整合到Prox 1中并对其进行调节。的 本研究的目的是获得一个详细的机制，了解淋巴管生成信号如何触发 通过生长因子和炎性细胞因子以磷酸化的形式转导到Prox 1蛋白， 调节其特性，并最终协调淋巴发育和功能。我们假设 RAF-ERK-RSK信号级联介导各种淋巴管生成信号并使PROX 1磷酸化 S79，并且这种修饰显著改变了Prox 1在淋巴发育过程中的生物学特性 和功能为了解决这些假设，我们建议研究磷酸化S79对行为的影响， 的PROX 1，并阐明调节淋巴管生成的ERK-RSK 2-PROX 1（S79）轴下， 生理和病理条件。最后，我们将制造突变小鼠模型，使组织- 用其磷酸化突变体特异性地、有条件地替换内源性野生型Prox 1。使用这些 动物模型，我们将研究PROX 1 S79磷酸化突变对淋巴发育的影响， 在健康和疾病中发挥作用。总之，拟议的研究将定义Prox 1 S79磷酸化， 活化淋巴管的生物标志物，调节生理和病理淋巴管生成。的 这项研究的结果不仅将对我们目前对功能的理解产生重大影响， PROX 1作为淋巴系统主要调节因子的模式，也为血管疾病提供了更广泛的见解。 发展和功能。

PROJECT SUMMARY The homeodomain transcription factor PROX1 is necessary and sufficient for induction and maintenance of lymphatic endothelial cell identity. It not only plays an essential role in the initial lymphatic reprogramming, expansion, maturation and maintenance, but also directs formation of luminal and lymphovenous valves. Although Prox1 has been intensively studied for its function, structure, and regulation, it remains unclear how such numerous developmental and environmental signals are efficiently incorporated to and regulate Prox1. The objective of this study is to gain a detailed mechanistic understanding of how lymphangiogenic signals triggered by growth factors and inflammatory cytokines are transduced to Prox1 protein in the form of phosphorylation, modulate its properties, and eventually orchestrate lymphatic development and function. We hypothesize that the RAF-ERK-RSK signal cascade mediates various lymphangiogenic signals and phosphorylates PROX1 at S79, and that this modification significantly alters the biological properties of Prox1 during lymphatic development and function. To address these hypotheses, we propose to study of the impact of phospho-S79 to the behaviors of PROX1, and to elucidate the regulation of lymphangiogenesis by the ERK-RSK2-PROX1 (S79) axis under the physiological and pathological conditions. Finally, we will generate mutant mouse models that allow a tissue- specific, conditional replacement of the endogenous wild type Prox1 with its phospho-mutants. Using these animal models, we will study of the impact of PROX1 S79 phospho-mutation to lymphatic development and function in health and disease. In summary, the proposed study will define how Prox1 S79 phosphorylation, as a biomarker of activated lymphatic vessels, regulates physiological and pathological lymphangiogenesis. The outcome of this study will not only deliver a significant impact on our current understanding of the functional mode of PROX1 as the master regulator of the lymphatic system, but also offer broader insights into vascular development and function.