Molecular Basis of Familial Paraganglioma

家族性副神经节瘤的分子基础

基本信息

批准号：
9057471
负责人：
LOUIS JAMES MAHER
金额：
$ 29.69万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9057471
关键词：
Abdomen Address Affect Animal Model Biochemical Blood Glucose Caenorhabditis elegans Cancer Etiology Cells Citric Acid Cycle Common Neoplasm Cultured Cells DNA Defect Development Dioxygenases Educational process of instructing Enzymes Epigenetic Process Family Gene Expression Genes Genetic Genomics Goals Health Hereditary Paraganglioma Histones Human Hypoxia Inducible Factor Knowledge Laboratories Loss of Heterozygosity Malignant Neoplasms Mammalian Cell Metabolic Metabolism Mixed Function Oxygenases Modeling Molecular Monitor Mus Mutate Nematoda Neuroendocrine Cell Neurons Neurosecretory Systems Oncogenes Oncogenic Paraganglioma Patients Phenotype Preclinical Drug Evaluation Prevention approach Prevention therapy Procollagen-Proline Dioxygenase Proteins Recipe Running Sampling Speed Succinate Dehydrogenase Succinates Testing Transgenic Organisms Tumor Suppressor Genes alpha ketoglutarate base cancer cell cancer therapy cell transformation egg fascinate gene therapy histone demethylase histone methylation inhibitor/antagonist interest knock-down loss of function loss of function mutation mouse model mutant neoplastic cell novel novel strategies novel therapeutics restoration tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Cancer cells have been likened to speeding cars. Mutated oncogenes hold down accelerator pedals; mutated tumor suppressor genes ruin brakes. Though often helpful, this analogy completely fails in the fascinating case of familial paraganglioma (PGL). Amazingly, PGL is a neuroendocrine cancer caused by loss of succinate dehydrogenase in the tricarboxylic acid (TCA) cycle of central metabolism. This is equivalent to severely disabling the engine of a car! How can loss-of-function mutations in a metabolic enzyme possibly be oncogenic, and why only in neuroendocrine cells? These irresistible biochemical questions drive this proposal, and answers will have significance for cancer therapy far beyond PGL. The central hypothesis is that succinate accumulation due to loss of SDH triggers neuroendocrine cell transformation by epigenetic effects resulting from inhibition of at least three different 2-ketoglutarate- dependent dioxygenase enzymes that produce succinate as a byproduct. It is as if the speeding car of cancer loses control because the driver is intoxicated by fumes from a faulty engine! We hypothesize that dioxygenase inhibition alters gene expression by novel epigenetic effects including (i) inappropriate activation of Hypoxia Inducible Factor (HIF), (ii) accumulation of methylated histones, and (iii) depletion of genomic 5-hydroxymethylcytosine. The strategy is to characterize PGL tumors and mammalian cells lacking SDH function, and to develop a nematode model of PGL for drug screening in Caenorhabditis elegans. Aim 1 will seek evidence for dioxygenase inhibition in primary human PGL tumor samples. Aim 2 will explore dioxygenase inhibition in cultured human and mouse cells lacking SDH. Aim 3 will monitor PGL tumorigenesis in mice with conditional SDH disruption. Finally, Aim 4 will develop a C. elegans model of PGL to uncover new therapeutics.

描述（由申请人提供）：癌细胞被比作超速行驶的汽车。突变的癌基因会抑制油门踏板；突变的肿瘤抑制基因会破坏刹车。尽管这种类比通常很有帮助，但在家族性副神经节瘤（PGL）这一令人着迷的案例中却完全失败了。令人惊奇的是，PGL 是一种神经内分泌癌，是由中枢代谢的三羧酸 (TCA) 循环中琥珀酸脱氢酶缺失引起的。这相当于让一辆汽车的引擎严重失灵！代谢酶的功能丧失突变如何可能致癌，为什么只在神经内分泌细胞中？这些不可抗拒的生化问题推动了这一提议，其答案对于癌症治疗的意义将远远超出 PGL。中心假设是，由于 SDH 损失导致的琥珀酸积累会通过表观遗传效应触发神经内分泌细胞转化，而表观遗传效应是由于抑制至少三种不同的 2-酮戊二酸依赖性双加氧酶（产生琥珀酸副产物）而产生的。就好像那辆超速行驶的癌症汽车失去了控制，因为驾驶员被故障发动机排出的烟雾所陶醉！我们假设双加氧酶抑制通过新的表观遗传效应改变基因表达，包括（i）缺氧诱导因子（HIF）的不适当激活，（ii）甲基化组蛋白的积累，以及（iii）基因组5-羟甲基胞嘧啶的消耗。该策略是表征 PGL 肿瘤和缺乏 SDH 功能的哺乳动物细胞，并开发用于秀丽隐杆线虫药物筛选的 PGL 线虫模型。目标 1 将寻找原代人 PGL 肿瘤样本中双加氧酶抑制的证据。目标 2 将探索培养的缺乏 SDH 的人和小鼠细胞中双加氧酶的抑制作用。目标 3 将监测条件性 SDH 破坏小鼠中 PGL 肿瘤的发生。最后，Aim 4 将开发 PGL 的线虫模型，以发现新的疗法。