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： Chyle在胸膜空间中的先天或新生儿积累是胸膜积液的最常见原因影响10,000分之一的出生，死亡率在20-60％之间。自发的新生儿患者 Chyle的积累经常表现出双侧胸膜积液，严重的呼吸窘迫，呼吸呼吸和氰化物，表明压缩对肺依从性和气体交换损害的机械影响在肺泡。尽管Bartloet博士将Chyle积累在胸膜空间中作为淋巴异常 1633年，尚未完全定义其形成和治疗的机制。最近的研究揭示了产前淋巴功能的要求，排出胸膜液并促进出生时肺的通胀，这是可行性所必需的。为此，在普列拉（Pleura）内，广泛的淋巴管网络，肋间空间，小动脉和静脉的血管周空间以及末端的结缔组织呼吸道支气管维持液体稳态并促进有效的气体交换。异常扩张这些淋巴血管（称为淋巴管氏症）经常与新生儿thyos积液相关，未成熟的肺和严重的呼吸窘迫，死亡率。即使鲁道夫·维尔乔博士描述了最早于1856年，新生儿肺淋巴管症是基本的因果病因和治疗选择保持难以捉摸。我们的初步研究确定了病理MAPK激活之间意外的因果关系和小鼠和人类的淋巴管症。淋巴MAPK的病理激活导致严重的肺淋巴管症，胸膜空间中Chyle的积累以及完全的致死性。初步分析诊断患有淋巴管症的患者的人类病理组织样本显示MAPK持续淋巴内皮细胞内的激活并概括了鼠表型。机械上，全基因组磷酸化的MAPK占用屏幕显示了对进化保守的直接调节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信号通路建立并维护特定的淋巴管的转录程序发展。此外，拟议的研究将确定特定激酶和转录因子相互作用以调节发育中的MAPK的染色质募集淋巴脉管系统。一组提出的研究对于理解信号的方式具有广泛的意义途径与染色质修饰的转录因子相交，以调节器官特异性的发展淋巴脉管系统，可能高度适用于整个先天性血管疾病的领域。