TSC Proteins in the Lymphatic Vasculature

淋巴管系统中的 TSC 蛋白

基本信息

批准号：
10735519
负责人：
Ying Yang
金额：
$ 69.7万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735519
关键词：
Adverse effects Affect Alleles Apoptosis Brain Breathing Cell Nucleus Cessation of life Chest Chest Pain Chronic Disease Chyle Chylothorax Communicable Diseases Cyst Data Development Diarrhea Dietary Fats Disease Disease Management Ear Embryo Extravasation FOXC2 gene FOXO1A gene Genes Genetic Hamartoma Human Immune Impairment Individual Kidney Knock-out Knockout Mice Link Liquid substance Lung Lymph Lymphatic Lymphatic Capillaries Lymphatic Endothelial Cells Mesentery Molecular Molecular Target Mus Mutation Nuclear Oral Ulcer Organ Outcome Pathogenicity Pathologic Patients Permeability Persons Pharmaceutical Preparations Phenotype Pleura Proliferating Proteins Proto-Oncogene Proteins c-akt Pulmonary Inflammation Reporting Respiratory Failure Risk Role SLC12A3 gene Signal Pathway Signal Transduction Sirolimus Skin Smooth Muscle Smooth Muscle Myocytes Symptoms TSC1 gene TSC2 gene Tamoxifen Thinking Thoracic Duct Time Tissues Tuberous Sclerosis Tuberous sclerosis protein complex Western Blotting absorption cell type compliance behavior dietary effective therapy hypercholesterolemia knock-down knockout animal loss of function lymph flow lymphatic development lymphatic dysfunction lymphatic malformations lymphatic valve lymphatic vasculature lymphatic vessel novel novel strategies phosphoproteomics postnatal prevent response rib bone structure shear stress small hairpin RNA transcription factor transcriptome sequencing tumor

项目摘要

Tuberous Sclerosis Complex (TSC) is a chronic disease that is caused by mutations in the genes TSC1 or TSC2. The disease affects 2 million people worldwide and there is no cure for TSC disease. Symptoms include formation of large tumors called hamartomas in various organs of the body, including the brain, the kidney, and the lung. One of the severe complications associated with these tumors is chylothorax, which is the accumulation of chyle in the space between the pleura and chest cavity. Chyle is a milky fluid that originates from lymphatic vessels draining dietary fats. Chylothorax can cause difficulty breathing, tachypnea, chest pain, respiratory failure, and death. Although chylothorax indicates malfunctioning lymphatic vessels in TSC patients, the current dogma is that tumors compress/obstruct the lymphatic vessels near the lung resulting in leakage, and it remains unknown whether TSC mutations in lymphatic endothelial cells are a causative factor of chylothorax. Thus, a significant unmet need is to determine whether lymphatic vessels are involved in TSC disease and delineate the pathological changes of the lymphatic vasculature due to TSC loss-of-function, which will identify new signaling pathways and molecular targets for this disease. Our preliminary data show that lymphatic-specific deletion of the Tsc genes in mice leads to chylothorax and is accompanied by a severe loss of lymphatic valves. These data suggest that the lymphatic vasculature is involved in TSC disease and regressing lymphatic valves allow lymph to flow backwards into the paravertebral and intercostal lymphatic capillaries, which causes lymph leakage from the thoracic duct into the chest cavity. Aim 1 will determine pathological changes in the lymphatic vasculature upon genetic deletion of Tsc genes, Aim 2 will identify the molecular mechanisms by which loss of Tsc1 or Tsc2 causes the loss of lymphatic valves, and Aim 3 will investigate novel approach to reverse lymphatic valve loss in the Tsc knockouts. It is highly anticipated that these aims will identify new pathogenic features of TSC disease and new signaling pathways affected by loss of TSC signaling.

结节硬化症复合物（TSC）是一种慢性疾病，是由基因TSC1或TSC2中突变引起的。该疾病在全球影响200万人，无法治愈TSC疾病。症状包括在人体各个器官中，包括大脑，肾脏和肺。与这些肿瘤相关的严重并发症之一是乳糜胸，这是积累 Chyle在胸腔和胸腔之间的空间中。 Chyle是一种乳液，起源于淋巴排干饮食脂肪的血管。乳胸会引起呼吸困难，呼吸呼吸，胸痛，呼吸道失败和死亡。尽管乳胸表明TSC患者的淋巴管故障，但电流教条是肿瘤压缩/阻塞肺附近的淋巴管，导致泄漏，并保持尚不清楚淋巴内皮细胞中的TSC突变是否是脑曲局部的病因。因此，重要的未满足的需求是确定淋巴管是否参与TSC疾病并描述 TSC功能丧失引起的淋巴管的病理变化，该功能将确定新的信号传导该疾病的途径和分子靶标。我们的初步数据表明，淋巴特定的缺失小鼠中的TSC基因会导致乳胸，并伴随着严重的淋巴瓣损失。这些数据表明淋巴脉管系统参与TSC疾病并恢复淋巴瓣膜允许淋巴向后流入副脑和肋骨间淋巴毛细血管，这会导致淋巴泄漏胸管进入胸腔。 AIM 1将确定淋巴管的病理变化在TSC基因的遗传缺失后，AIM 2将确定TSC1或TSC2丢失的分子机制导致淋巴瓣的损失，AIM 3将研究逆转淋巴瓣损失的新方法在TSC淘汰赛中。备受期待的，这些目标将确定TSC疾病的新致病特征以及受TSC信号丢失影响的新信号通路。