Ethanol and aldehyde dehydrogenases in health and disease

乙醇和乙醛脱氢酶在健康和疾病中的作用

基本信息

批准号：
10018801
负责人：
DARIA MOCHLY-ROSEN
金额：
$ 64.45万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-09-30 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018801
关键词：
4 hydroxynonenal Abbreviations Acetaldehyde Acids Adenosine Triphosphate Age Alcohol consumption Alcohol dehydrogenase Alcoholic Beverages Aldehydes Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Animal Model Asians Benign Biochemical California Cell Death Cell model Cells Chronic Chronic Disease DNA Sequence Databases Data Defect Disease Disease Progression Dynamin Electronic Mail Environment Enzymes Epidemiology Ethanol Ethanol Metabolism Ethnic group Exhibits Exposure to Face Flushing Food Functional disorder Gene Library General Population Genotype Glyceraldehyde-3-Phosphate Dehydrogenases Grant Health Heavy Drinking Human Human Genome Human Pathology Impairment Injury International Agency for Research on Cancer Knock-out Lead Lipid Peroxidation Malignant Neoplasms Malignant neoplasm of esophagus Metabolism Mission Mitochondria Mitochondrial Matrix Modeling Morbidity - disease rate Mus Mutation Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Neurons Nitroglycerin Nucleic Acids Other Genetics Oxidative Stress Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phenotype Point Mutation Population Prevalence Protein Kinase C Proteins Reactive Oxygen Species Recombinants Reporting Research Research Support Risk Role Source Structure Structure-Activity Relationship Surveys Taiwan Testing Therapeutic Intervention United States National Institutes of Health Variant Work adduct aldehyde dehydrogenases binge drinking carcinogenicity cell injury dementia risk fluorescence activated cell sorter device genetic analysis human disease human model human old age (65+)induced pluripotent stem cell interest macromolecule mitochondrial dysfunction mortality mouse model neurofilament overexpression oxidative damage precision medicine small molecule tetramethylrhodamine methyl ester

项目摘要

Ethanol is metabolized by alcohol dehydrogenase to acetaldehyde, a known toxic agent that can form adducts on macromolecules. The levels of acetaldehyde and other aldehydes increase under oxidative stress, and the increase in aldehydic load is associated with a number of common human pathologies. Relevant to this proposal, increased aldehydic load contributes to neurodegeneration. A major defense from acetaldehyde and from other aldehydes that we generate or are exposed to from the environment is the mitochondrial matrix enzyme, aldehyde dehydrogenase 2 (ALDH2). Ten years ago, our research (supported by this grant) demonstrated a critical cytoprotective role for ALDH2: direct activation with a small molecule that we discovered, Alda-1, reduces oxidative damage in a number of cell and animal models of human diseases. A common human inactivating point mutation in ALDH2 (ALDH2*2), present in ~560 million East Asians, increases the cell injury and cell death by aldehydic load induced by high levels of ethanol or by oxidative stress, and Alda-1 treatment reduces this injury. Because ALDH2*2 mutation is so common, we propose the HYPOTHESIS that additional ALDH2 deficiencies may exist in significantly large numbers in populations other than East Asians. Supported by our preliminary data, in AIM 1 we plan to identify and characterize new common ALDH2 variants, determine the effect of these variants on ethanol-induced acetaldehyde metabolism in human cells and identify new small molecules (ALDH2 activators; Aldas) that correct these newly identified inactive variants. Mounting evidence connects aldehydic load and neurodegenerative diseases, such as Alzheimer’s disease (AD). There is also a significant increased risk for AD among carriers of ALDH2*2 genotype. Because mitochondrial dysfunction contributes to neurodegeneration and aldehydes cause mitochondrial dysfunction, and because there is a correlation between frequent alcohol consumption, increased risk of dementia and a potential role for acetaldehyde in neurodegeneration, we plan to test our second HYPOTHESIS that inactivating variants of ALDH2 and the higher acetaldehyde levels following ethanol consumption contribute to mitochondrial dysfunction and thus to neurodegeneration. In AIM 2, we will characterize new ALDH2-inactive variants and their effect on mitochondrial structure and function in the presence of ethanol in cultured neuronal cells, in AD patient-derived cells, and in an AD mouse model expressing inactivating ALDH2 variants, in the presence or absence of chronic exposure to moderate levels of ethanol. Over 80% of the population in the US consumes alcoholic beverages. As ~1-2% of people over the age of 65 and ~30% of people over 80 develop AD, the possibility that ethanol consumption contributes to the progression of the disease in the general population and in patients deficient in ALDH2 activity, and the identification of a potential therapeutic intervention, are the subjects of this proposal.

乙醇由酒精脱氢酶代谢为乙醛，乙醛是一种已知的有毒剂，可以形成加合物在大分子上。乙醛和其他醛的水平在氧化应激下增加，并且醛负荷增加与许多常见的人类病理有关。与此提案有关，醛负荷增加有助于神经退行性。乙醛和其他的主要防御我们从环境中产生或暴露于环境的醛是线粒体基质酶，醛脱氢酶2（ALDH2）。十年前，我们的研究（由这笔赠款支持）证明了 ALDH2的关键细胞保护作用：我们发现的小分子直接激活Alda-1会减少许多细胞和人类疾病的动物模型中的氧化损伤。 ALDH2（ALDH2*2）中的一个常见人类灭活点突变，存在于约5.6亿东亚人，通过高水平的乙醇或氧化应激引起的醛增加增加细胞损伤和细胞死亡， ALDA-1治疗减少了这种伤害。因为ALDH2*2突变非常普遍，所以我们提出了假设除了以外的其他人群中，可能存在其他ALDH2缺陷东亚。在我们的初步数据的支持下，在AIM 1中，我们计划识别和表征新的常见 AldH2变体，确定这些变体对乙醇诱导的乙醛代谢的影响细胞并鉴定新的小分子（ALDH2激活剂； ALDA），这些分子纠正了这些新鉴定的非活性变体。越来越多的证据将醛负荷和神经退行性疾病连接起来，例如阿尔茨海默氏病（AD）。 ALDH2*2基因型载体中AD的风险也大大增加。因为线粒体功能障碍会导致神经退行性和醛引起线粒体功能障碍，因为经常饮酒，痴呆风险增加与潜在的作用之间存在相关性乙醛在神经退行性中，我们计划检验第二个假设，即灭活变体乙醇消耗后的ALDH2和较高的乙醛水平有助于线粒体功能障碍，因此是神经退行性的。在AIM 2中，我们将表征新的AldH2-Inactive变体和它们对培养神经元细胞中乙醇存在的线粒体结构和功能的影响，AD 在存在或缺乏长期暴露于现代乙醇水平。美国超过80％的人口占用酒精卧室。〜65岁以上的人中约有1-2％在80多个开发广告中，约有30％的人，乙醇消耗有助于进步的可能性普通人群和患者缺乏ALDH2活性的疾病的鉴定潜在的治疗干预是该提案的主题。