Therapeutic Strategy for LAM (Lymphangioleiomyomatosis)

LAM（淋巴管平滑肌瘤病）的治疗策略

• 批准号: 8768835
• 负责人: N. Tony Eissa
• 金额: $ 153.78万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-18 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768835
• 关键词: Adverse effects; Adverse event; Affect; Angiomyolipoma; Autistic Disorder; Autophagocytosis; Behavior; Cell Differentiation process; Cell Proliferation; Cell membrane; Cell model; Cell-Cell Adhesion; Cells; Clinical Trials; Combined Modality Therapy; Cyst; Data; Diagnosis; Diffusion; Disease; Dose; Down-Regulation; E-Cadherin; Embryo; Epithelial; Female; Fibroblasts; Future; Genetic Transcription; Goals; Growth; Infiltration; Infiltrative Growth; Lead; Lung; Lung diseases; Lymphangioleiomyomatosis; Mental Retardation; Mesenchymal; Monitor; Mus; Mutation; Normal Cell; Oncogenic; Oral; Organ failure; Patients; Pattern; Pharmaceutical Preparations; Phase; Plasma; Play; Primary Neoplasm; Proteins; Pulmonary Function Test/Forced Expiratory Volume 1; Quality of life; Rattus; Research; Role; Safety; Seizures; Serum; Smooth Muscle; Somatic Mutation; Staging; Structure of parenchyma of lung; TSC2 gene; Testing; Therapeutic; Tissues; Total Lung Capacity; Transcription Repressor/Corepressor; Tuberous sclerosis protein complex; Tumor Suppressor Genes; Vascular Endothelial Growth Factor D; Vital capacity; Walking; Woman; Xenograft procedure; cell motility; cell type; design; human FRAP1 protein; immunosuppressed; improved; inhibition of autophagy; inhibitor/antagonist; mTOR Inhibitor; meetings; mouse model; mutant; novel therapeutics; prevent; safety testing; src-Family Kinases; tumor; tumor growth

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in tuberous sclerosis complex 1 (TSC1) or TSC2. TSC is characterized by tumors in wide range of tissues, seizures, mental retardation, autism, and organ failure. Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease affecting 35% of women with TSC and is characterized by growth of abnormal and potentially metastatic atypical smooth muscle-like LAM cells within the lungs. Sporadic LAM can develop in women without TSC, owing to somatic mutations in TSC2 gene. It has been suggested that LAM cells undergo epithelial-mesenchymal transition (EMT). Src kinases are key regulators of cellular proliferation, motility, invasiveness and EMT. The central hypothesis of this proposal is that ¿Src is activated in LAM cells and that increased Src activation contributes to down-regulation of E-cadherin and raises the oncogenic abilities of these cells. Thus, Src inhibition represents a potential therapeutic strategy to up-regulate E-cadherin in LAM cells, suppress EMT and reduce their oncogenic and metastatic potential.¿ The increased Src activity in TSC2-deficient cells is likely caused by inhibition of autophagy associated with hyper-activation of mTOR. Autophagy has been shown to be responsible for degradation of active Src. We propose to explore the use of Src inhibitors in LAM.

结节性硬化症（TSC）是由结节性硬化症1（TSC 1）或TSC 2突变引起的常染色体显性遗传疾病。TSC的特征在于广泛组织中的肿瘤、癫痫发作、精神发育迟滞、自闭症和器官衰竭。淋巴管平滑肌瘤病（LAM）是一种进行性囊性肺病，影响35%的TSC女性，其特征是肺内异常和潜在转移性非典型平滑肌样LAM细胞的生长。由于TSC 2基因的体细胞突变，在没有TSC的女性中可以发生散发性LAM。已经提出LAM细胞经历上皮-间充质转化（EMT）。Src激酶是细胞增殖、运动性、侵袭性和EMT的关键调节因子。该建议的中心假设是，在LAM细胞中Src被激活，并且Src激活的增加有助于下调E-钙粘蛋白并提高这些细胞的致癌能力。因此，Src抑制代表了一种潜在的治疗策略，可以上调LAM细胞中的E-cadherin，抑制EMT并降低其致癌和转移潜力。TSC 2缺陷细胞中增加的Src活性可能是由与mTOR超活化相关的自噬抑制引起的。自噬已被证明是负责降解的活性Src。我们建议探索Src抑制剂在LAM中的应用。