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Epigenetic regulation of lymphatic development

淋巴管发育的表观遗传调控

基本信息

批准号：
10662551
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/10662551
关键词：
Affect Alveolus Automobile Driving Basement membrane Bilateral Biology Birth Blood Vessels Cells Characteristics Chest Chromatin Chyle Chylothorax Collagen Connective Tissue Consensus Cyanosis Cytoplasm Defect Deposition Development Diagnosis Drainage procedure Embryo Endothelium Etiology Exhibits Extravasation 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 Phenotype Phosphorylation Phosphotransferases Pleura Pleural Pleural effusion disorder Proteins Regulation Regulatory Element Repression 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 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 pharmacologic 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：先天性或新生儿乳糜液在胸腔积聚是胸腔积液最常见的原因。影响10000名新生儿中的1名，死亡率在20%-60%之间。新生儿自发性心绞痛乳糜聚积常表现为双侧胸腔积液、严重呼吸窘迫、呼吸急促和青紫，提示压迫对肺顺应性和气体交换障碍的机械性影响在肺泡里。尽管Bartloet医生将胸膜腔内乳糜液的积聚确定为淋巴异常在1633年，它们的形成和处理机制还没有完全确定。最近的研究表明，产前淋巴功能需要排出胸腔积液，促进出生时肺充盈，是生存所必需的。为了做到这一点，胸膜内广泛的淋巴管网络，肋间间隙、小动脉和小静脉的血管周围间隙以及终末结缔组织。呼吸性细支气管会维持体液平衡，促进有效的气体交换。异常扩张其中被称为淋巴管扩张症的淋巴管通常与新生儿乳糜液有关，肺未成熟，严重呼吸窘迫并死亡。即使鲁道夫·维肖博士描述了 1856年新生儿肺淋巴管扩张症的病因和治疗选择仍然难以捉摸。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联系以及小鼠和人类的淋巴管扩张。淋巴管MAPK的病理性激活导致重症肺淋巴管扩张，乳酪在胸膜腔内堆积，并完全致死。初步分析了我国目前存在的淋巴管扩张症患者的人体病理组织样本显示持续的MAPK 在淋巴管内皮细胞内激活，并概括了小鼠的表型。从机械上讲，全基因组磷酸化MAPK占位筛选揭示了进化上保守的淋巴管结构和功能所需的遗传程序。这项研究计划旨在确定如何 MAPK信号通路为淋巴管建立和维持一个特定的转录程序发展。此外，拟议的研究将确定特定的激酶和转录因子相互作用调节发育中肺组织中MAPK的染色质募集淋巴管系统。所提出的一系列研究对于理解信号如何与染色质修饰的转录因子相交的通路调节器官特异性的发育淋巴血管系统，可高度适用于整个领域的先天性血管疾病。