Prostaglandin biosynthesis: a novel therapeutic target in TSC disorders

描述（由申请人提供）：多发性硬化症（TSC）是一种常染色体显性遗传疾病，具有多系统表现，包括癫痫发作、精神发育迟滞、自闭症以及脑、心脏、皮肤、肾脏和肺部肿瘤。80%的TSC患者发生肾血管平滑肌脂肪瘤;也发生囊肿和癌。TSC是由TSC 1或TSC 2中的种系失活突变引起的，TSC 1或TSC 2分别编码错构瘤蛋白（TSC 1）和块茎蛋白（TSC 2）。TSC 1和TSC 2作为复合物发挥作用，以抑制哺乳动物雷帕霉素靶蛋白（mTOR）复合物1（mTORC 1），TSC患者的肿瘤显示mTORC 1的过度活化。mTORC 1是蛋白质合成、细胞生长和细胞代谢的关键调节因子。用雷帕霉素或依维莫司（mTORC 1抑制剂）治疗可部分减少TSC中肾血管平滑肌脂肪瘤和脑肿瘤的体积，但停止治疗后肿瘤会重新生长。雷帕霉素的长期益处和危害尚不确定。我们的中心假设是TSC 2的缺失增强了磷脂酶A2-环氧合酶-胰高血糖素受体（PAL 2-COX 1/2-EP 3）途径中组分的表达和活性，从而导致胰高血糖素的产生增强并促进了TSC相关肿瘤的发展。本提案的长期目标是确定考克斯-2和前列腺素生物合成的TSC 2依赖性和mTORC 1非依赖性上调的分子机制和意义，从而促进拟南芥素作为疾病严重程度的生物标志物的潜在应用，以及前列腺素抑制剂作为TSC中发生的肿瘤的治疗方法的开发，以及在非TSC患者中发生的具有TSC 1/TSC 2参与的肿瘤。

DESCRIPTION (provided by applicant): Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with multi-system manifestations including seizures, mental retardation, autism, and tumors in the brain, heart, skin, kidney, and lung. 80% of TSC patients develop renal angiomyolipomas; cysts and carcinomas also occur. TSC is caused by germline inactivating mutations in TSC1 or TSC2, which encode hamartin (TSC1) and tuberin (TSC2), respectively. TSC1 and TSC2 function as a complex to inhibit mammalian target of rapamycin (mTOR) complex 1 (mTORC1), and tumors from TSC patients show hyperactivation of mTORC1. mTORC1 is a key regulator of protein synthesis, cell growth and cellular metabolism. Treatment with rapamycin or everolimus, mTORC1 inhibitors, partially decreases the volume of renal angiomyolipomas and brain tumors in TSC, but tumors regrow when treatment is discontinued. The long-term benefits and hazards of rapamycin are uncertain. Our central hypothesis is that loss of TSC2 enhances the expression and activity of components in phospholipase A2-cyclooxygenases-prostaglanin receptors (PAL2-COX1/2-EP3) pathways, and thereby leads to enhanced production of prostaglandins and promotes TSC-related tumor development. The long-term goal of this proposal is to identify the molecular mechanisms and significance of TSC2-dependent and mTORC1-independent up-regulation of COX-2 and prostaglandin biosynthesis, and thereby facilitate the potential application of prostaglandins as biomarkers of disease severity, and the development of prostaglandin inhibitors as therapeutic approaches for tumors occurring in TSC, and tumors with TSC1/TSC2 involvement occurring in non-TSC patients.