Mechanisms of Alcohol Toxicity and Kidney Damage

项目摘要 酒精消费导致全球约6%的死亡。仍然迫切需要 了解酒精中毒和肾脏疾病的生化机制，如慢性酒精中毒 摄入已被证明在急性肾损伤的发展中起关键作用， 酒精相关性肝病的死亡率。不可否认的是，过度饮酒的影响 这是导致肾损伤的直接途径，但这种作用的机制仍不清楚。这 该提案将关键的初步数据整合到一个创新的假设中，即酒精代谢导致 破坏乙酰依赖性细胞信号传导和改变基因表达谱，有助于近端 肾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 这导致整个细胞的负面后果，包括改变基因重编程和细胞 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因素， 下游肾脏病理，如近端肾小管功能障碍。因此，我们提出了一个创新的 研究酒精中毒如何引起肾损伤的方法。我们将调查拟议中的 具体目标：具体目标1：确定慢性饮酒如何改变肾脏组蛋白乙酰化 使用组织空间转录组学分析基因表达谱。具体目标2：检查改变的近端 慢性酒精代谢导致的肾小管病理学和蛋白质组学活性。这些目标将是 使用多学科方法进行询问，该方法将整合病理分析、定量质量 用于蛋白质组学、酶测定和组织形态学基因表达的光谱分析，以及创新的 数据分析和生物信息学。这项研究的一个关键成果将是加强对 酒精代谢影响肾功能的机制需要进一步的治疗干预， 改善肾脏疾病。

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.