Dysregulated cholesterol homeostasis, caused by lysosomal/autophagy dysfunction, mediates pancreatitis

由溶酶体/自噬功能障碍引起的胆固醇稳态失调可介导胰腺炎

基本信息

批准号：
10587086
负责人：
ANNA S. GUKOVSKAYA
金额：
$ 35.48万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587086
关键词：
Acids Acinar Cell Applied Genetics Automobile Driving Autophagocytosis Biogenesis Cell Survival Cell physiology Cells Cholesterol Cholesterol Homeostasis Clinical Research Cytoplasmic Organelle Disease Disease model Drug Modulation Exocrine pancreas Functional disorder Genetic Goals Human Impairment Incidence Inflammation Inflammatory Inflammatory Response Intervention Lysosomal Storage Diseases Lysosomes Measures Mediating Mitochondria Modeling Molecular Molecular Target Morbidity - disease rate Mus Mutation Organ Model Oxidative Stress Pancreas Pancreatitis Pathogenesis Pathogenicity Pathologic Pathway interactions Pharmaceutical Preparations Play Pre-Clinical Model Public Health Recycling Regulation Research Role Severities Severity of illness Simvastatin Testing United States National Institutes of Health acute pancreatitis clinically relevant effective therapy mortality mouse model novel pharmacologic response transcription factor

项目摘要

Summary/Abstract Acute pancreatitis (AP) is a disorder with significant morbidity and mortality that lacks treatments. The lysosomal/autophagy pathway – a key catabolic mechanism by which cells eliminate damaged cytoplasmic organelles – is impaired in both experimental and human pancreatitis. Further, genetic alterations specifically targeting autophagy or lysosomes cause spontaneous pancreatitis in mice. These findings implicate impaired lysosomal/autophagy pathways in initiating and driving pancreatitis. The mechanisms through which disordering of these pathways causes the disease remain, however, unknown. Studies in other organs and disease models showed a critical role for lysosomal/autophagy pathways in regulating cholesterol homeostasis, essential for cell viability and function. Moreover, recent studies indicate that use of cholesterol-lowering drugs, statins, is associated with lower incidence of AP and decreased mortality. However, there is little known about cholesterol metabolism in the exocrine pancreas and its’ dysregulation in pancreatitis. The effects of statins and other cholesterol-lowering drugs on acinar cell cholesterol homeostasis and AP responses have not been studied. We here propose a novel hypothesis for the pathogenic mechanism of pancreatitis: that lysosomal/autophagy dysfunction causes dysregulation of acinar cell cholesterol homeostasis, leading to mitochondrial oxidative stress and pathologic responses of pancreatitis. Our preliminary results indicate that both preclinical models and human pancreatitis are associated with profound dysregulation of cholesterol homeostasis in acinar cells, and that lysosomal/autophagy dysfunction associated with AP plays a key mediatory role in these effects. They further show the role of cholesterol dysregulation in disease severity, in particular mitochondrial oxidative stress and inflammation. The hypothesis will be tested in three Specific Aims: 1). Investigate dysregulation of acinar cell cholesterol homeostasis in experimental and human pancreatitis and its role in pancreatitis responses. 2). Determine the role of cholesterol dysregulation in pancreatitis caused by disrupted lysosomal/autophagy pathways. 3). Examine the role of cholesterol dysregulation in mitochondrial oxidative stress leading to inflammation in pancreatitis. The proposed research is significant because it will establish cholesterol metabolism as a clinically relevant modulator of pancreatitis severity and identify potential molecular targets, amenable for pharmacologic intervention, to normalize cholesterol metabolism and thus reduce pancreatitis severity. In particular, we will elucidate the mechanisms of the effects of statins and other cholesterol-modulating drugs on pancreatitis.

摘要/摘要急性胰腺炎（AP）是一种缺乏治疗的发病率和死亡率的疾病。溶酶体/自噬途径 - 一种关键分解代谢机制，通过该机制消除细胞受损的细胞质细胞器 - 在实验性和人类胰腺炎中受到损害。此外，遗传改变了靶向自噬或溶酶体会导致小鼠的赞成胰腺炎。这些发现受损启动和驱动胰腺炎中的溶酶体/自噬途径。混乱的机制但是，这些途径导致该疾病仍然未知。其他器官和疾病模型的研究溶酶体/自噬途径在稳定胆固醇稳态中表现出至关重要的作用，这对于细胞至关重要生存力和功能。此外，最近的研究表明，毒药的使用是他汀类药物的使用与较低的AP事件和改善死亡率有关。但是，关于胆固醇鲜为人知外分泌胰腺中的代谢及其在胰腺炎中的失调。他汀类药物和其他尚未研究腺泡细胞胆固醇稳态和AP反应的降低胆固醇药物。我们在这里，提出了一种关于胰腺炎的致病机制的新假设：该溶酶体/自噬功能障碍引起腺泡细胞胆固醇稳态失调，导致线粒体氧化应激胰腺炎的病理反应。我们的初步结果表明，临床前模型和人类胰腺炎都与腺泡细胞中胆固醇稳态的严重失调，以及溶酶体/自噬功能障碍与AP相关联在这些效果中起关键的介体作用。他们进一步展示了胆固醇的作用疾病严重程度的失调，特别是线粒体氧化应激和炎症。该假设将以三个具体目的进行检验： 1）。研究在实验性和人类胰腺炎以及它在胰腺炎反应中的作用。 2）。确定胆固醇失调在溶酶体/自噬中断引起的胰腺炎中的作用途径。 3）。检查胆固醇失调在线粒体氧化应激中的作用，导致炎症胰腺炎。拟议的研究很重要，因为它将建立胆固醇代谢作为临床相关胰腺炎的调节剂严重程度并确定潜在的分子靶标，可用于药理学干预，以使胆固醇代谢正常化，从而降低胰腺炎的严重程度。特别是，我们会阐明他汀类药物和其他胆固醇调节药物对胰腺炎的作用的机制。