Hyperhomocysteinemia, S-adenosylhomocysteine Accumulation, and Epigenetics

描述（由申请人提供）：血浆总同型半胱氨酸（tHcy）水平升高，称为高同型半胱氨酸血症（HHcy），与许多人类疾病的发病率和死亡率增加有关，包括冠心病、中风、痴呆、阿尔茨海默病、糖尿病、骨质疏松症、癌症、神经管缺陷和肝脏脂肪变性。与tHcy升高相关的疾病的数量和种类表明，它可能影响非常基本的细胞功能。同型半胱氨酸是由s -腺苷型同型半胱氨酸（SAH）水解产生的中间代谢物，SAH是涉及甲基供体s -腺苷型蛋氨酸（SAM）的甲基化反应的副产物。我们实验室和其他实验室的研究表明，血浆中tHcy的升高与组织中细胞内SAH的升高有关。由于SAH是一种有效的甲基转移反应抑制剂，例如那些参与基因表达调节的甲基转移反应，这可能指出一种将tHcy升高与多种疾病状态联系起来的可能机制。因此，本提案的总体目标是检验假设

DESCRIPTION (provided by applicant): Elevated levels of plasma total homocysteine (tHcy), termed hyperhomocysteinemia (HHcy), are associated prospectively with increased incidence and mortality of many human diseases including coronary heart disease, stroke, dementia, Alzheimer's disease, diabetes, osteoporosis, cancer, neural tube defects and steatosis of the liver. The number and variety of diseases associated with elevated tHcy suggests that it may affect very basic cellular functions. Homocysteine is an intermediary metabolite produced from the hydrolysis of S-adenosylhomocysteine (SAH), which is a by-product of methylation reactions involving the methyl-donor S-adenosylmethionine (SAM). Studies from our lab and others show that elevations in tHcy in plasma are associated with elevations of intracellular SAH in tissues. Since SAH is a potent inhibitor of methyl-transfer reactions, such as those involved in the regulation of gene expression, this could point to a possible mechanism linking elevated tHcy to diverse disease states. Therefore, the overall goal of this proposal is to test the hypothesis that severe HHcy causes elevations in tissue SAH that results in inhibition of chromatin methylation and alters cellular gene expression in vivo. The proposed experiments will utilize an inducible genetic and a nutritional mouse model that each induce severe HHcy by a different mechanism. There are three specific aims: (1) Determine if HHcy is associated with elevated tissue SAH levels and global hypomethylation of DNA and histones. (2) Determine how HHcy affects gene-specific transcript levels, DNA, and histone methylation. (3) Determine if overexpression of SAH hydrolase can reverse the hypomethylation and gene expression phenotypes. Achieving these aims will lead to understanding the mechanism by which elevated tHcy causes disease and will give us new insight into potential interventions that could delay or eliminate the onset of homocysteine related diseases.