Understanding the epigenetic basis of human familial paraganglioma

了解人类家族性副神经节瘤的表观遗传学基础

• 批准号: 8760210
• 负责人: Yeng Fransoua Her
• 金额: $ 4.14万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2016-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8760210
• 关键词: Address; Bacteria; Cell Line; Cells; Cessation of life; Citric Acid Cycle; Cranial nerve palsies; Cultured Cells; Cytosine; DNA; Defect; Development; Dioxygenases; Enzymes; Epigenetic Process; Genes; Goals; Headache; Health; Hereditary Paraganglioma; Histology; Histones; Human; Hypertension; Hypoxia Inducible Factor; Knowledge; Laboratories; Malignant - descriptor; Malignant Neoplasms; Metabolic; Metabolism; Methylation; Mixed Function Oxygenases; Modeling; Mus; Neuroendocrine Cell; Neuroendocrine Tumors; Neurosecretory Systems; Oncogenic; Palpitations; Paraganglioma; Pre-Clinical Model; Prevention; Procollagen-Proline Dioxygenase; Research; Specimen; Starvation; Succinate Dehydrogenase; Succinates; Symptoms; Tinnitus; Warburg Effect; aerobic glycolysis; alpha ketoglutarate; base; cell growth; gene replacement; gene therapy; human tissue; interest; knock-down; loss of function; mutant; neoplastic cell; novel strategies; novel therapeutic intervention; public health relevance; restoration; tissue culture; tissue/cell culture; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Understanding the epigenetic basis of human familial paraganglioma. Our laboratory is interested in understanding how defects in metabolism can promote tumorigenesis. Specifically, we study familial paraganglioma (PGL), a neuroendocrine cancer, as a model that exemplifies metabolic derangement. Familial PGL displays autosomal dominant inheritance and is due to loss of both copies of genes encoding subunits of succinate dehydrogenase (SDH), a tricarboxylic acid (TCA) cycle enzyme. Loss of SDH function is particularly interesting because it exemplifies the Warburg effect of aerobic glycolysis, a mysterious feature of many cancers. To date, there is no clear explanation for how loss of SDH function leads to tumor formation in neuroendocrine cells. Furthermore, there is no preclinical model to study this cancer. The long-term goal of this proposal is to understand how loss of function of SDH induces PGL in neuroendocrine cells. This knowledge will provide new approaches to PGL prevention and treatment. Our central hypothesis is that dioxygenase inhibition by succinate accumulation causes oncogenic epigenetic effects including activation of Hypoxia Inducible Factor (HIF), accumulation of histone methylation, and depletion of 5-hydroxymethyl-deoxycytosine (5hmdC). Our strategy is to develop three models to study succinate accumulation. These include (1) human familial PGL tumor histology specimens, (2) SDHB lentiviral knockdown human tissue culture cells, and (3) a mouse SDHC-/- cell line. Aim 1 will examine the effects of SDH loss in PGL tumor specimens. Aim 2 will determine effects of SDH knockdown in tissue culture cells and if these effects can be overcome by SDH gene replacement or increasing 2-ketoglutarate levels. Finally, Aim 3 will characterize the effects of SDH loss in a mouse SDHC-/- cell line.

描述（申请人提供）：了解人类家族副神经节瘤的表观遗传学基础。我们实验室对了解代谢缺陷如何促进肿瘤发生很感兴趣。具体来说，我们研究家族性副神经节瘤（PGL），一种神经内分泌癌，作为代谢紊乱的典范。家族性PGL表现为常染色体显性遗传，是由于编码琥珀酸脱氢酶（SDH）亚基的基因的两个拷贝丢失，这是一种三羧酸（TCA）循环酶。SDH功能的丧失特别有趣，因为它体现了有氧糖酵解的Warburg效应，这是许多癌症的一个神秘特征。迄今为止，对于SDH功能的丧失如何导致神经内分泌细胞的肿瘤形成，还没有明确的解释。此外，还没有临床前模型来研究这种癌症。本提案的长期目标是了解SDH功能丧失如何诱导神经内分泌细胞的PGL。这些知识将为PGL的预防和治疗提供新的途径。我们的中心假设是，琥珀酸积累对双加氧酶的抑制会导致致癌的表观遗传效应，包括缺氧诱导因子（HIF）的激活、组蛋白甲基化的积累和5-羟甲基脱氧胞嘧啶（5hmdC）的消耗。我们的策略是开发三种模型来研究琥珀酸盐的积累。这些包括(1)人类家族性PGL肿瘤组织学标本，(2)SDHB慢病毒敲除的人类组织培养细胞，以及(3)小鼠SDHC-/-细胞系。目的1将研究SDH丢失对PGL肿瘤标本的影响。目的2将确定SDH敲低对组织培养细胞的影响，以及这些影响是否可以通过SDH基因替代或增加2-酮戊二酸水平来克服。最后，Aim 3将描述SDH缺失对小鼠SDHC-/-细胞系的影响。