Epigenetic regulation of lymphatic development

淋巴管发育的表观遗传调控

基本信息

批准号：
10540097
负责人：
Chinmay M Trivedi
金额：
$ 60.97万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10540097
关键词：
Affect Alveolus Automobile Driving Basement membrane Bilateral Biology Birth Cells Characteristics Chest Chromatin Chyle Chylothorax Collagen Connective Tissue Consensus Cyanosis Defect Deposition Development Diagnosis Drainage procedure Embryo Endothelium Etiology Exhibits Fluid Balance Gases Genes Genetic Genetic Transcription Homeostasis Human Impairment KRAS2 gene KRASG12D Laminin Link Liquid substance Lung Lung Compliance Lymphangiectasis Lymphatic Lymphatic Diseases Lymphatic Endothelial Cells Lymphatic Endothelium Lymphatic System Lymphatic function MAP Kinase Gene MAPK Signaling Pathway Pathway MAPK1 gene Mechanics Membrane Proteins Mitogen-Activated Protein Kinase Inhibitor Modeling Molecular Mus Mutation Neonatal Newborn Infant Nidogen Nuclear Oncogenic Pathogenesis Pathologic Pathway interactions Patients Pharmacology Phenotype Phosphotransferases Pleura Pleural Pleural effusion disorder Proteins Regulation Regulatory Element Research Respiratory Failure Respiratory distress Role Signal Pathway Signal Transduction Somatic Mutation Structure Structure of respiratory bronchiole Terminal Bronchiole Testing Tissue Sample Tissues Transcriptional Regulation Vascular Diseases arteriole base crosslink effective therapy effusion epigenetic regulation experimental study gain of function mutation genome-wide human model improved lung maturation lymphatic development lymphatic malformations lymphatic vasculature lymphatic vessel mortality mouse model mutant neonatal mice neonatal patient novel organ growth postnatal prenatal prevent programs recruit transcription factor venule

项目摘要

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.

项目摘要/摘要：先天性或新生儿胸膜腔内乳糜积聚是胸腔积液的最常见原因影响万分之一的新生儿，死亡率在 20-60% 之间。自发性新生儿患者乳糜积聚经常表现出双侧胸腔积液、严重呼吸窘迫、呼吸急促和紫绀，表明压缩对肺顺应性和气体交换损害的机械影响在肺泡中。尽管 Bartloet 博士将胸膜腔内乳糜积聚视为淋巴管异常 1633年，其形成和治疗机制尚未完全明确。最近的研究表明产前淋巴功能需要排出胸腔积液并促进出生时肺部充气，这是生存能力所必需的。为了实现这一目标，胸膜内有一个广泛的淋巴管网络，肋间隙、小动脉和小静脉的血管周围间隙以及终末结缔组织和呼吸细支气管维持液体稳态并促进有效的气体交换。异常扩张这些淋巴管，称为淋巴管扩张，经常与新生儿乳糜积液相关，肺部不成熟，以及严重的呼吸窘迫和死亡。尽管鲁道夫·菲尔肖 (Rudolf Virchow) 博士描述早在 1856 年就发现了新生儿肺淋巴管扩张症，其根本原因和治疗方案仍然难以捉摸。我们的初步研究发现病理性 MAPK 激活之间存在意想不到的因果关系以及小鼠和人类的淋巴管扩张。淋巴 MAPK 的病理激活导致严重的肺部疾病淋巴管扩张，胸膜腔内乳糜积聚，并完全致死。初步分析诊断为淋巴管扩张症的患者的人体病理组织样本显示持续的 MAPK 淋巴管内皮细胞内的激活并重现了小鼠表型。从机械上来说，全基因组磷酸化 MAPK 占据筛选揭示了进化上保守的直接调控淋巴管结构和功能所需的遗传程序。该研究计划旨在确定如何 MAPK 信号通路建立并维持淋巴管的特定转录程序发展。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发育中肺内 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传导如何进行具有广泛的意义途径与染色质修饰转录因子相交叉，调节器官特异性的发育淋巴管系统，可以高度适用于先天性血管疾病的整个领域。