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:
  • 金额:
    $ 69.7万
  • 依托单位:
  • 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

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.
多发性硬化症(TSC)是一种由TSC 1或TSC 2基因突变引起的慢性疾病。 这种疾病影响了全世界200万人,目前还没有治愈TSC疾病的方法。症状包括 在身体的各种器官中形成称为错构瘤的大肿瘤,包括脑,肾, 肺与这些肿瘤相关的严重并发症之一是乳糜胸, 在胸膜和胸腔之间的空间中的乳糜。乳糜是一种乳状液体, 排出食物脂肪的血管。乳糜胸可引起呼吸困难、呼吸急促、胸痛、呼吸困难、 失败和死亡。虽然乳糜胸表明TSC患者的淋巴管功能障碍,但目前 教条是肿瘤压迫/阻塞肺附近的淋巴管,导致渗漏,并且它仍然存在。 淋巴管内皮细胞中的TSC突变是否是乳糜胸的致病因素尚不清楚。因此 显著未满足的需求是确定淋巴管是否参与TSC疾病并描绘淋巴管的结构。 由于TSC功能丧失导致的淋巴管系统的病理变化,这将识别新的信号传导 这种疾病的分子靶点。我们的初步数据显示, 小鼠中的Tsc基因导致乳糜胸,并伴有淋巴瓣的严重丧失。这些数据 提示淋巴管系统参与TSC疾病,淋巴管瓣膜退化使淋巴 回流到椎旁和肋间毛细淋巴管,这导致淋巴泄漏, 胸导管进入胸腔目的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Tsc 1或Tsc 2缺失的分子机制, 导致淋巴瓣丧失,Aim 3将研究逆转淋巴瓣丧失的新方法 在TSC淘汰赛中。高度期望这些目标将确定TSC疾病的新致病特征 和新的信号传导途径受到TSC信号传导丢失的影响。

项目成果

期刊论文数量(0)
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Ying Yang其他文献

Ying Yang的其他文献

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{{ truncateString('Ying Yang', 18)}}的其他基金

Molecular mechanisms enhancing lymphatic valve formation
增强淋巴瓣形成的分子机制
  • 批准号:
    10543483
  • 财政年份:
    2019
  • 资助金额:
    $ 69.7万
  • 项目类别:
Molecular mechanisms enhancing lymphatic valve formation
增强淋巴瓣形成的分子机制
  • 批准号:
    10331300
  • 财政年份:
    2019
  • 资助金额:
    $ 69.7万
  • 项目类别:

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