Epigenetic regulation of lymphatic development

项目总结/摘要： 先天性或新生儿乳糜积聚在胸膜腔是最常见的原因胸腔积液 每10，000名新生儿中就有1人受到影响，死亡率在20- 60%之间。新生儿自发性 乳糜积聚常表现为双侧胸腔积液、严重呼吸窘迫、呼吸急促， 紫绀，提示压迫对肺顺应性的机械作用和气体交换的损害 在肺泡中。虽然Bartloet医生确定乳糜在胸膜腔的积聚是淋巴异常 1633年，它们的形成和治疗机制尚未完全确定。最近的研究表明， 需要产前淋巴功能来排出胸腔积液，并在出生时促进肺的膨胀， 是生存所必需的。为了实现这一点，胸膜内广泛的淋巴管网络， 肋间隙、小动脉和小静脉的血管周围间隙以及末端的结缔组织 和呼吸性细支气管维持流体稳态并促进有效的气体交换。异常扩张 称为淋巴管扩张症，经常与新生儿乳糜泻有关， 肺发育不全和严重的呼吸窘迫导致死亡尽管鲁道夫·魏尔肖博士描述了 新生儿肺淋巴管扩张症早在1856年，潜在的病因和治疗方案 仍然难以捉摸我们的初步研究确定了病理性MAPK激活与 以及小鼠和人类的淋巴管扩张。淋巴管MAPK的病理性激活导致严重的肺 淋巴管扩张、乳糜在胸膜腔中积聚和完全致死。的初步分析 来自诊断为淋巴管扩张症的患者的人类病理组织样品显示持续的MAPK 淋巴管内皮细胞内的活化，并概括了小鼠表型。机械地， 全基因组磷酸化MAPK占有率筛选揭示了一个进化上保守的 淋巴管结构和功能所需的遗传程序。这项研究旨在确定如何 MAPK信号通路建立并维持淋巴管特异性转录程序 发展此外，拟议的研究将确定特定激酶和 转录因子相互作用调节MAPK的染色质募集 淋巴管系统这组拟议的研究对于理解信号如何传递具有广泛的意义。 途径与染色质修饰转录因子交叉，以调节器官特异性 淋巴管系统，并可高度适用于整个先天性血管疾病领域。

PROJECT SUMMARY / ABSTRACT: Congenital or neonatal accumulation of chyle in the pleural space is the most common cause of pleural effusion affecting 1 in 10,000 births with mortality rates between 20-60%. Neonatal patients with a spontaneous accumulation of chyle frequently exhibit bilateral pleural effusion, severe respiratory distress, tachypnea, and cyanosis, suggesting the mechanical effect of compression on lung compliance and impairment of gas exchange in alveoli. Although Dr. Bartloet established accumulation of chyle in the pleural space as a lymphatic anomaly in 1633, the mechanism for their formation and treatment have not been fully defined. Recent studies reveal the requirement of prenatal lymphatic function to drain pleural fluid and promote the inflation of lungs at birth, which is required for viability. To accomplish this, an extensive network of lymphatic vessels within the pleura, the intercostal space, the perivascular spaces of arterioles and venules, and the connective tissue of the terminal and respiratory bronchioles maintain fluid homeostasis and promote effective gas exchange. Abnormal dilation of these lymphatic vessels, known as lymphangiectasia, is frequently associated with neonatal chylous effusion, immature lungs, and severe respiratory distress with mortality. Even though Dr. Rudolf Virchow described neonatal pulmonary lymphangiectasia as early as 1856, the underlying causal etiology and treatment options remain elusive. Our preliminary studies identify an unexpected causal link between pathological MAPK activation and lymphangiectasia in mice and humans. Pathological activation of lymphatic MAPK causes severe pulmonary lymphangiectasia, accumulation of chyle in the pleural space, and complete lethality. Preliminary analyses of human pathological tissue samples from patients diagnosed with lymphangiectasia revealed sustained MAPK activation within lymphatic endothelial cells and recapitulated the murine phenotype. Mechanistically, the genome-wide phosphorylated MAPK occupancy screen revealed direct regulation of an evolutionarily conserved genetic program required for lymphatic vessel structure and function. This research program aims to identify how the MAPK signaling pathway establishes and maintains a specific transcriptional program for lymphatic vessel development. In addition, proposed studies will identify the mechanisms by which specific kinases and transcription factors interact to regulate the chromatin recruitment of MAPK within developing pulmonary lymphatic vasculature. The set of proposed studies has broad significance for understanding how signaling pathways intersect with chromatin-modifying transcription factors to regulate the development of organ-specific lymphatic vasculature and could be highly applicable to the entire field of congenital vascular diseases.