Prostaglandin biosynthesis: a novel therapeutic target in TSC disorders

描述(申请人提供)：结节性硬化症(TSC)是一种常染色体显性遗传性疾病，具有多系统表现，包括癫痫、智力低下、自闭症以及大脑、心脏、皮肤、肾脏和肺的肿瘤。80%的TSC患者发生肾血管平滑肌脂肪瘤；也会发生囊性和癌。TSC是由TSC1或TSC2的种系失活突变引起的，TSC1或TSC2分别编码Hamartin(TSC1)和Tuberin(TSC2)。TSC1和TSC2作为一种复合体抑制哺乳动物雷帕霉素靶标(MTOR)复合体1(MTORC1)，而TSC患者的肿瘤显示mTORC1的过度激活。MTORC1是蛋白质合成、细胞生长和细胞代谢的关键调节因子。雷帕霉素或伊波利莫斯是mTORC1抑制剂，治疗可以部分缩小TSC中肾血管肌脂瘤和脑瘤的体积，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，TSC2的缺失增强了磷脂酶A2-环氧合酶-前列腺素受体(PAL2-COX1/2-EP3)通路中各组分的表达和活性，从而导致前列腺素的产生增加，促进了TSC相关肿瘤的发展。这项建议的长期目标是确定TSC2依赖和mTORC1非依赖上调COX-2和前列腺素生物合成的分子机制和意义，从而促进前列腺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治疗方法的开发，以治疗发生在TSC和非TSC1/TSC2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.