Prox1 Phosphorylation in Lymphatic Development and Function

项目总结 同源结构域转录因子PROX1是诱导和维持 淋巴管内皮细胞的特性。它不仅在最初的淋巴重新编程中起着至关重要的作用， 扩张、成熟和维持，但也指导管腔和淋巴静脉瓣膜的形成。 虽然Prox1的功能、结构和调控已被广泛研究，但目前仍不清楚它是如何 如此众多的发育和环境信号被有效地整合到Prox1中并对其进行调控。这个 这项研究的目的是详细了解淋巴管生成信号是如何触发的 通过生长因子和炎性细胞因子以磷酸化的形式转导Prox1蛋白， 调节其属性，并最终协调淋巴的发育和功能。我们假设 RAF-ERK-RSK信号通路介导多种淋巴管生成信号，并磷酸化PROX1。 S79，并且这种修饰显著改变了Prox1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-S79对行为的影响 并阐明ERK-RSK2-PROX1(S79)轴对淋巴管生成的调节作用。 生理和病理条件。最后，我们将产生突变的小鼠模型，允许组织- 用内源野生型Prox1的磷酸突变体进行特定的、有条件的替换。使用这些 动物模型，我们将研究PROX1 S79磷酸化突变对淋巴发育和 在健康和疾病中发挥作用。总之，拟议的研究将定义Prox1 S79如何磷酸化，如 一种激活淋巴管的生物标志物，调节生理和病理淋巴管的生成。这个 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 PROX1作为淋巴系统的主要调节器的模式，也提供了对血管的更广泛的见解 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.