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Mechanisms of HIF1 alpha mediated dysregulated skeletal muscle proteostasis in alcoholic liver disease

HIF1α介导的酒精性肝病骨骼肌蛋白稳态失调的机制

基本信息

批准号：
10579341
负责人：
Nicole Welch
金额：
$ 17.91万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579341
关键词：
Address Adverse effects Alcohol consumption Alcoholic Liver Cirrhosis Alcoholic Liver Diseases Alcohols Ammonia Autophagocytosis Award Biological Assay Biopsy Specimen Career Choice Chromatin Chronic Disease Cirrhosis Citric Acid Cycle Clinical Collaborations Complex Data Degradation Pathway Development Environment Ethanol Exposure to FRAP1 gene Fellowship Foundations Funding Genetic Transcription Goals HIF1A gene Heart failure Hepatic Human Hyperammonemia Hypoxia Hypoxia Inducible Factor Impairment In Vitro Institution Kidney Failure Label Link Liver diseases Mediating Mentors Metabolic Molecular Molecular Target Morbidity - disease rate Mus Muscle Muscle Fibers Muscle Proteins Muscular Atrophy National Institute on Alcohol Abuse and Alcoholism Ohio Outcome Oxygen Patients Phenotype Phosphotransferases Physicians Physiological Pilot Projects Post-Translational Protein Processing Pre-Clinical Model Prevalence Protein Biosynthesis Reporter Reporting Research Research Methodology Research Personnel Research Project Grants Scientist Signal Transduction Signaling Molecule Skeletal Muscle Stress Testing Time Tissues Training Translational Research Transposase United States Validation Work alcohol consequences alcohol exposure alcohol response alcohol testing alcohol use disorder alpha ketoglutarate biobank career development clinical training clinical translation clinically significant effective therapy experimental study gain of function hepatic ureagenesis in vivo inhibitor liver transplantation loss of function lung failure metabolic abnormality assessment mitochondrial dysfunction mortality muscle form muscle strength novel preservation programs proteostasis response sarcopenia skeletal muscle wasting targeted treatment therapeutically effective tissue injury transcription factor uptake

项目摘要

The prevalence of alcohol use disorders and consequent tissue injury, primarily alcoholic liver disease (ALD) continue to increase. Skeletal muscle loss or sarcopenia is a consistent abnormality in patients with ALD and is associated with adverse clinical outcomes that include increased mortality, other complications of liver disease and poor post-liver transplant outcomes. We have recently reported more severe muscle loss and a greater rate of muscle loss in patients with alcoholic cirrhosis compared with those in other causes of cirrhosis. Despite the high clinical significance of sarcopenia in ALD there are no effective therapeutic options because the underlying mechanisms are not well understood. We also reported that ethanol, directly and indirectly via impaired hepatic ammonia disposal and consequent hyperammonemia, results in a sarcopenic phenotype with dysregulated protein homeostasis (proteostasis). In preliminary studies, we have shown mitochondrial dysfunction in response to ethanol and hyperammonemia. We also noted that ethanol results in cataplerosis or loss of tricarboxylic acid (TCA) cycle intermediates, specifically α-ketoglutarate (αKG) an inhibitor of HIF1α. Consistently, unbiased approaches (assay for transposase accessible chromatin sequencing), and targeted experiments showed oxygen independent stabilization of muscle hypoxia inducible factor-1α (HIF1α) with ammonia. In pilot studies, we observed an increased expression of REDD1, a transcriptional target of HIF1α and a negative regulator of the mammalian target of rapamycin complex 1 (mTORC1) that maintains skeletal muscle proteostasis with functional responses. We also noted relative preservation of muscle mass during hyperammonemia in muscle specific deletion of HIF1α mice. These observations formed the basis for our hypothesis that ethanol induced hyperammonemia causes cataplerosis of αKG with oxygen independent stabilization and impaired proteostasis and sarcopenia. We will test this hypothesis by testing if ethanol stabilizes HIF1α in skeletal muscle, and determine the mechanisms of stabilization of muscle HIF1α. Ethanol treatment in vitro in myotubes and in vivo in mice with loss and gain of function of HIF1α and its regulatory molecules will be used for these studies We will also test how metabolic perturbations regulate HIF1α stabilization and consequent molecular and functional responses in our preclinical models. Validation of key observations will be done in human muscle tissue from our biorepository. The proposed studies will enhance our understanding of the mechanisms of sarcopenia in ALD and lay the foundation for targeted therapeutics. This award will provide the support and time for the applicant for a supervised research career development in translational research. The applicant works with NIAAA funded independent investigators in the Northern Ohio Alcohol Center and her mentor developed the field of sarcopenia in liver disease. The institutional environment is highly supportive of her career path towards becoming an independent physician scientist focusing on mechanistic approaches to address unmet clinical needs in patients with alcohol use disorders.

酒精使用障碍的患病率和随之而来的组织损伤，主要是酒精性肝病（ALD）