The Molecular and Genetic Pathogensis of LAM

LAM 的分子和遗传发病机制

• 批准号: 9358732
• 负责人: Elizabeth P Henske
• 金额: $ 69.21万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9358732
• 关键词: Address; Alleles; Autophagocytosis; Biogenesis; Biological Markers; Blood; CCL2 gene; Cell Count; Cells; Chronic; Clinical; Clinical Trials; Collaborations; Cyst; Data; Development; Disease; Dissection; Doctor of Philosophy; Dose; Extramural Activities; FRAP1 gene; Future; Gene Frequency; Genes; Genetic; Intramural Research Program; Link; Loss of Heterozygosity; Lung; Lymphangiogenesis; Lymphangioleiomyomatosis; Metabolism; MicroRNAs; Molecular; Molecular Genetics; Monomeric GTP-Binding Proteins; Mosaicism; Mosses; Mutation; Nodule; Patients; Pharmaceutical Preparations; Pleural effusion disorder; Pulmonary function tests; Renal Angiomyolipoma; Research; Resources; Respiratory physiology; Risk; Serum; Severity of illness; Sirolimus; Source; Surrogate Markers; TSC1/2 gene; TSC2 gene; Tissues; Toxic effect; Tuberous sclerosis protein complex; United States National Institutes of Health; Up-Regulation; Vascular Endothelial Growth Factor D; Woman; Work; analog; candidate marker; cell growth; cell type; combinatorial; design; diagnostic biomarker; monocyte; mutant; next generation sequencing; novel marker; novel therapeutics; overexpression; patient biomarkers; personalized strategies; programs; protein complex; response biomarker; risk minimization; sensor; treatment response; tumor

 DESCRIPTION (provided by applicant): Lymphangioleiomyomatosis (LAM) is a destructive multi-system disease of women characterized by cystic lung destruction, renal angiomyolipomas, and chylous pleural effusions. Lymphangiogenesis is prominent in pulmonary LAM nodules and serum VEGF-D is diagnostic biomarker of LAM. The majority of LAM cells carry bi-allelic inactivating mutations in the tuberous sclerosis complex (TSC) genes and circulating LAM cells with TSC2 loss of heterozygosity can be detected in the blood. The TSC protein complex inhibits the mammalian/mechanistic target of rapamycin (mTORC1) via the small GTPase Rheb (Fig.1). mTORC1 acts as a molecular sensor that regulates cell growth, metabolism, autophagy, and microRNA biogenesis. Pivotal clinical trials have demonstrated clinical benefit from treatment with sirolimus (Rapamycin) or its analogs (Rapalogs) in LAM and TSC. Collectively these data indicate that Rapamycin is an effective suppressive therapy for LAM. However, lung function decline resumes and tumors regrow when the drug is discontinued. Therefore, therapy must be used chronically - perhaps lifelong. This highlights the urgent unmet need for novel therapeutic strategies in LAM and TSC and/or mechanisms to allow Rapamycin to be dosed at the lowest effective level, to maximize benefit and minimize risk. This UO1 brings together a unique team of leaders in LAM research to address key unanswered questions with high clinical impact. First, what are the fundamental mechanisms leading to lymphangiogenesis in LAM? Second, can circulating LAM cell burden be quantitated through "next generation" sequencing and used as a biomarker of LAM? Third, will finer dissection of the genetic basis of sporadic LAM reveal generalized low-level TSC2 mosaicism? Fourth, can biomarkers including VEGF-D and microRNA be used to develop personalized strategies for sirolimus dosing? Narrative: This UO1 brings together a unique team of leaders in lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC) to address key unanswered questions with high clinical impact. First, what are the fundamental mechanisms leading to lymphangiogenesis in LAM? Second, can circulating LAM cell burden be quantitated through "next generation" sequencing and used as a biomarker of LAM? Third, will finer dissection of the genetic basis of sporadic LAM reveal generalized low-level TSC2 mosaicism? Fourth, can biomarkers including VEGF-D and microRNA be used to develop personalized strategies for Sirolimus dosing?

 描述（由应用提供）：淋巴管肌瘤病（LAM）是一种具有囊性肺部破坏，肾血管肌瘤和猫胸腔积液的妇女的破坏性多系统疾病。淋巴管生成在肺LAM结节中很突出，血清VEGF-D是LAM的诊断生物标志物。大多数LAM细胞在结节性硬化症复合物（TSC）基因中携带双推性突变，并且可以在血液中检测到具有杂合性TSC2丧失的循环LAM细胞。 TSC蛋白复合物通过小的GTPase RHEB抑制雷帕霉素（MTORC1）的哺乳动物/机械靶标（图1）。 MTORC1充当调节细胞生长，代谢，自噬和microRNA生物发生的分子传感器。关键的临床试验表明，在LAM和TSC中使用Sirolimus（雷帕霉素）或其类似物（Rapalogs）的治疗所带来的临床益处。这些数据共同表明雷帕霉素是对LAM的有效抑制疗法。但是，当药物停用时，肺功能下降和肿瘤改革。因此，必须长期使用治疗 - 也许是终生。这突出了对LAM和TSC中新型治疗策略的紧急需求和/或机制，即允许雷帕霉素以最低的有效水平剂量，以最大程度地提高收益并最大程度地降低风险。 该UO1汇集了LAM研究中独特的领导者团队，以解决具有较高临床影响的关键未解决问题。首先，导致LAM淋巴管生成的基本机制是什么？其次，可以通过“下一代”测序定量循环的lam细胞伯嫩，并用作LAM的生物标志物？第三，对零星LAM的遗传基础的解剖会揭示出普遍的低级TSC2镶嵌性吗？第四，包括VEGF-D和MicroRNA在内的生物标志物可以用于制定Sirolimus剂量的个性化策略吗？ 叙述：这种UO1汇集了一个独特的淋巴结肌瘤病（LAM）和结节性硬化症复合物（TSC）的独特领导者团队，以对临床影响很高的关键未解决的问题解决关键的未解决问题。首先，导致LAM淋巴管生成的基本机制是什么？其次，可以通过“下一代”测序定量循环的lam细胞伯嫩，并用作LAM的生物标志物？第三，对零星LAM的遗传基础的解剖会揭示出普遍的低级TSC2镶嵌性吗？第四，包括VEGF-D和MicroRNA在内的生物标志物可以用于制定Sirolimus剂量的个性化策略吗？