Mechanisms of Alcohol Toxicity and Kidney Damage

酒精中毒和肾脏损害的机制

基本信息

批准号：
10371787
负责人：
Kristofer S. Fritz
金额：
$ 22.35万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-25 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10371787
关键词：
Acetylation Acute Renal Failure with Renal Papillary Necrosis Alanine Transaminase Albumins Alcohol consumption Alcohols Atrophic Basic Science Biochemical Biochemical Pathway Bioinformatics Biological Assay Biological Markers Blood Urea Nitrogen Cell Death Cells Cessation of life Chronic Creatinine Data Data Analyses Development Epigenetic Process Ethanol Metabolism Ethanol toxicity Fibrosis Functional disorder Gene Expression Genes Genetic Glycosylated Hemoglobin Goals Health Heavy Drinking Hepatitis Histologic Histone Acetylation Histones Human Inflammation Injury to Kidney Kidney Kidney Diseases LCN2 gene Laboratories Liver Liver diseases Lysine Maps Mass Spectrum Analysis Measures Medical Meta-Analysis Metabolic Metabolism Modeling Morphology Nuclear Outcomes Research Pathologic Pathology Play Post-Translational Protein Processing Protein Acetylation Proteins Proteinuria Proteomics Proximal Kidney Tubules Publishing Renal Tissue Renal function Renal tubule structure Research Research Project Grants Risk Route Scheme Serum Signal Transduction Structure Techniques Therapeutic Intervention Tissue Sample Tissues Tubular formation alcohol consequences alcohol effect base chronic alcohol ingestion epidemiology study innovation insight interdisciplinary approach interstitial lipid metabolism mortality nephrogenesis novel renal damage transcriptomics

项目摘要

Project Summary Alcohol consumption contributes to approximately 6% of worldwide deaths. There remains a pressing need for understanding the biochemical mechanisms underlying alcohol toxicity and kidney disease, as chronic alcohol ingestion has been shown to play a key role in the development of acute kidney injury associated with the mortality of alcohol-associated liver disease. It is undeniable that the effect of excessive alcohol consumption presents a direct route to kidney damage, yet the mechanisms underlying this effect remain unknown. This proposal integrates key preliminary data into an innovative hypothesis that alcohol metabolism leads to disrupted acetyl-dependent cellular signaling and altered gene expression profiles, contributing to proximal tubule damage and kidney disease. Alcohol metabolism is known to alter numerous biochemical pathways which leads to negative consequences throughout the cell, including altered genetic reprogramming and cell death. Therefore, alcohol-induced protein acetylation is likely a key initial driver of these changes and downstream kidney pathologies, such as proximal tubular dysfunction. Therefore, we present an innovative approach for investigating how alcohol toxicity induces kidney damage. We will investigate the proposed specific aims: Specific Aim 1: Determine how chronic alcohol consumption alters renal histone acetylation profiles and gene expression using tissue spatial transcriptomics. Specific Aim 2: Examine altered proximal tubule pathology and proteomic activity resulting from chronic alcohol metabolism. These aims will be interrogated utilizing a multidisciplinary approach that will integrate pathological analysis, quantitative mass spectrometry for proteomics, enzymatic assays, and tissue morphology gene expression, as well as innovative data analyses and bioinformatics. A key outcome of this research will be an enhanced understanding of the mechanisms by which alcohol metabolism impacts renal function to further therapeutic intervention and the amelioration of kidney disease.

项目摘要饮酒量约为全球死亡人数的6％。仍然需要理解酒精毒性和肾脏疾病的生化机制，作为慢性酒精摄入已显示在与该急性肾脏损伤的发展中起关键作用酒精相关肝病的死亡率。不可否认的是，过度饮酒的影响提出了肾脏损伤的直接途径，但这种效果的基础机制仍然未知。这提案将关键初步数据整合到一个创新的假设中，即酒精代谢导致乙酰基依赖性细胞信号传导和基因表达谱改变，有助于近端小管损伤和肾脏疾病。众所周知，酒精代谢会改变许多生化途径这会导致整个细胞的负面后果，包括改变遗传重编程和细胞死亡。因此，酒精诱导的蛋白质乙酰化可能是这些变化的关键初始驱动力，下游肾脏病理，例如近端管状功能障碍。因此，我们提出了创新的研究酒精毒性如何诱导肾脏损害的方法。我们将调查提议的具体目的：特定目标1：确定慢性酒精消耗如何改变肾脏组蛋白乙酰化使用组织空间转录组学的轮廓和基因表达。特定目标2：检查近端改变慢性酒精代谢引起的小管病理和蛋白质组学活性。这些目标将是利用多学科方法的询问，该方法将整合病理分析，定量质量用于蛋白质组学，酶试验和组织形态基因表达的光谱法以及创新数据分析和生物信息学。这项研究的关键结果将是对酒精代谢会影响肾功能进一步治疗干预的机制肾脏疾病的改善。