TSC Proteins in the Lymphatic Vasculature

结节性硬化症(TSC)是一种慢性疾病，由TSC1或TSC2基因突变引起。 这种疾病影响着全球200万人，目前还没有治愈TSC疾病的方法。症状包括 在身体的不同器官形成称为错构瘤的大肿瘤，包括大脑、肾脏和 肺部。与这些肿瘤相关的严重并发症之一是乳糜胸，这是积聚。 在胸膜和胸腔之间的空隙中有乳糜液。乳糜液是一种乳白色液体，源自淋巴管。 排出膳食脂肪的船只。乳糜胸会导致呼吸困难、呼吸急促、胸痛、呼吸困难。 失败和死亡。尽管乳糜胸提示TSC患者淋巴管功能障碍，但目前的 有一种说法认为，肿瘤压迫/阻塞肺附近的淋巴管，导致渗漏，并且 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 尚未得到满足的重大需求是确定淋巴管是否与TSC疾病有关，并描绘 TSC功能丧失导致淋巴管系统的病理变化，这将识别新的信号 这种疾病的途径和分子靶点。我们的初步数据显示，淋巴特异性缺失 小鼠的TSC基因会导致乳糜胸，并伴随着淋巴瓣的严重丧失。这些数据 提示淋巴管系统与TSC疾病有关，淋巴瓣膜退行性使淋巴 向后流入椎旁和肋间毛细淋巴管，导致淋巴渗漏。 胸腔导管进入胸腔。目标1将确定淋巴管系统的病理变化 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 导致淋巴瓣丢失，目标3将研究扭转淋巴瓣丢失的新方法 在TSC淘汰赛中。人们高度期待这些目标将识别TSC病的新的致病特征。 以及受TSC信号丢失影响的新的信号通路。

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.