Hyperhomocysteinemia, S-adenosylhomocysteine Accumulation, and Epigenetics

高同型半胱氨酸血症、S-腺苷同型半胱氨酸积累和表观遗传学

• 批准号: 8639583
• 负责人: WARREN D KRUGER
• 金额: $ 33.92万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639583
• 关键词: Adenosylhomocysteinase; Affect; Alleles; Alzheimer' s Disease; Amino Acids; Animals; Cell physiology; Chromatin; Complementary DNA; Coronary heart disease; Cystathionine beta-Synthase; DNA; DNA Methylation; Data; Dementia; Diabetes Mellitus; Diet; Disease; Epigenetic Process; Event; Fatty Liver; Gene Expression; Gene Expression Regulation; Genes; Genetic; Goals; Histones; Homocysteine; Homocystine; Human; Hydrolysis; Hyperhomocysteinemia; Incidence; Intervention; Lead; Link; Liver; Malignant Neoplasms; Measures; Metallothionein; Methionine; Methylation; Methyltransferase; Modeling; Mouse Strains; Mus; Neural Tube Defects; Nutritional; Osteoporosis; Pattern; Phenotype; Plasma; Play; Prevention; Proteins; Reaction; Research; Risk; S-Adenosylhomocysteine; S-Adenosylmethionine; Siblings; Spleen; Stroke; Testing; Tissues; Transcript; Transgenes; Zinc; brain tissue; drinking water; human disease; in vivo; inhibitor/antagonist; insight; molecular pathology; mortality; mouse model; novel; overexpression; promoter; public health relevance; research study

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.

描述（由申请人提供）：称为高体温性半胱氨酸血症（HHCY）的血浆总半胱氨酸（THCY）的水平升高与许多人类疾病的发病率和死亡率有关，包括冠心病，中风，痴呆，痴呆症，阿尔茨海默氏病，阿尔茨海默氏病，糖尿病，糖尿病，骨化症，癌症，癌症，癌症，癌症，癌症，癌症，癌症，癌症，癌症，癌症，癌症，癌症，癌症，癌症。与Thcy升高有关的疾病的数量和种类表明，它可能会影响非常基本的细胞功能。同型半胱氨酸是一种由S-腺苷甲基硬化半胱氨酸（SAH）的水解产生的中介代谢产物，它是涉及甲基二烯丙基甲基硫氨酸（SAM）的甲基化反应的副产品。我们实验室和其他实验室的研究表明，血浆中ThCY的升高与组织内细胞内SAH的升高有关。由于SAH是一种有效的甲基转移反应抑制剂，例如参与基因表达的调节的反应，这可能表明将升高THCY与多种疾病状态联系起来的可能机制。因此，该提议的总体目标是检验以下假设。 严重的HHCY导致组织SAH的升高，从而导致抑制染色质甲基化并改变体内细胞基因的表达。提出的实验将利用可诱导的遗传和营养小鼠模型，该模型各自通过不同的机制诱导严重的HHCY。有三个特定的目的：（1）确定HHCY是否与组织SAH水平升高以及DNA和组蛋白的全局甲基化相关。 （2）确定HHCY如何影响基因特异性转录水平，DNA和组蛋白甲基化。 （3）确定SAH水解酶的过表达是否可以逆转低甲基化和基因表达表型。实现这些目标将导致理解升高THCY引起疾病的机制，并使我们对可能延迟或消除同型半胱氨酸相关疾病发作的潜在干预措施有了新的见解。