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.

结节性硬化症 (TSC) 是一种由 TSC1 或 TSC2 基因突变引起的慢性疾病。这种疾病影响着全世界 200 万人，并且 TSC 疾病无法治愈。症状包括在身体的各个器官中形成称为错构瘤的大肿瘤，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，即积聚胸膜和胸腔之间的乳糜。乳糜是一种乳白色液体，源自淋巴管排出膳食脂肪的血管。乳糜胸可导致呼吸困难、呼吸急促、胸痛、呼吸困难失败和死亡。尽管乳糜胸表明 TSC 患者的淋巴管存在功能障碍，但目前的研究教条是肿瘤压缩/阻塞肺部附近的淋巴管导致渗漏，并且它仍然存在目前尚不清楚淋巴管内皮细胞中的 TSC 突变是否是乳糜胸的致病因素。因此，一个未满足的重要需求是确定淋巴管是否与 TSC 疾病有关并描绘出由于 TSC 功能丧失导致淋巴管系统发生病理变化，这将识别新的信号传导这种疾病的途径和分子靶点。我们的初步数据表明，淋巴特异性缺失小鼠体内的 Tsc 基因会导致乳糜胸，并伴有淋巴瓣膜的严重丧失。这些数据表明淋巴管系统与 TSC 疾病有关，并且淋巴瓣膜退化允许淋巴管回流到椎旁和肋间毛细淋巴管，导致淋巴液从胸导管进入胸腔。目标 1 将确定淋巴脉管系统的病理变化在 Tsc 基因遗传删除后，目标 2 将确定 Tsc1 或 Tsc2 丢失的分子机制导致淋巴瓣膜缺失，Aim 3 将研究逆转淋巴瓣膜缺失的新方法在 Tsc 淘汰赛中。高度期待这些目标将确定 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。