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）：癌细胞已比作超速汽车。突变的癌基因固定加速踏板；突变的肿瘤抑制基因破坏了制动器。尽管经常有帮助，但这种类比在家族性paraganglioma（PGL）的引人入胜的情况下完全失败了。令人惊讶的是，PGL是一种神经内分泌癌，由中枢代谢的三羧酸（TCA）周期中的琥珀酸脱氢酶丧失引起。这相当于严重禁用汽车的发动机！代谢酶的功能丧失突变如何可能是致癌性的，为什么仅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建议，答案对远远超出PGL的癌症治疗将具有重要意义。中心假设是，由于抑制至少三种不同的2-酮戊二酸酯依赖性的二氧酶酶而导致的表观遗传学作用导致SDH触发神经内分泌细胞的转化引起的琥珀酸盐积累，这些遗传效应产生了琥珀酸酯作为副产品。好像癌症的超速汽车失去了控制，因为驾驶员被故障发动机的烟雾陶醉！我们假设二加氧酶抑制通过新颖的表观遗传作用改变了基因表达，包括（i）低氧诱导因子（HIF），（ii）甲基化组蛋白的积累和（iii）基因组5-羟基甲基糖苷的耗竭。该策略是表征缺乏SDH功能的PGL肿瘤和哺乳动物细胞，并开发秀丽隐杆线虫药物筛查的PGL的线虫模型。 AIM 1将寻求对原代人PGL肿瘤样品中二氧酶抑制的证据。 AIM 2将探索缺乏SDH的培养的人和小鼠细胞中的双氧酶抑制。 AIM 3将监测有条件SDH破坏的小鼠中的PGL肿瘤发生。最后，AIM 4将开发PGL的秀丽隐杆线虫模型，以发现新的治疗剂。