Cholesterol-lowering drugs for treatment of pancreatitis: validation of a clinically significant novel therapeutic target and approach

用于治疗胰腺炎的降胆固醇药物：验证具有临床意义的新型治疗靶点和方法

• 批准号: 10585773
• 负责人: ANNA S. GUKOVSKAYA
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10585773
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; ATP Citrate (pro-S)-Lyase; Acids; Acinar Cell; Acute; Address; Adverse effects; Age; Amylases; Apoptosis; Automobile Driving; Autophagocytosis; Benefits and Risks; Biogenesis; Blood; Categories; Cell Death; Cell model; Cells; Cholelithiasis; Cholesterol; Cholesterol Homeostasis; Chronic; Clinical; Clinical Trials; Critical Pathways; Cytoplasmic Organelle; Disease; Enzymes; Etiology; Exclusion; Exocrine pancreas; FDA approved; Fibrosis; Functional disorder; Future; Healthcare; Healthcare Systems; Heavy Drinking; Hospitalization; Human; Impairment; Incidence; Inflammation; Inflammatory; Intervention; Islets of Langerhans; Lipase; Lysosomal Storage Diseases; Lysosomes; Malignant neoplasm of pancreas; Measures; Medical; Military Personnel; Modeling; Molecular; Mus; Mutation; Necrosis; Oxidoreductase; Pain; Pancreas; Pancreatitis; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Pre-Clinical Model; Prevalence; Preventive; Quality of life; Recycling; Regimen; Risk; Risk Assessment; Risk Factors; Role; Serum; Severities; Severity of illness; Simvastatin; Smoking; Speed; Therapeutic; Tissues; Toxic effect; Treatment Protocols; Trypsinogen; Validation; Veterans; cholesterol biosynthesis; clinically relevant; clinically significant; comparative; cost; drug development; effective therapy; immune cell infiltrate; injured; mouse model; neutrophil; new therapeutic target; novel strategies; pharmacologic; pre-clinical; response; therapeutic target

Pancreatitis is a common, potentially fatal, disease of the exocrine pancreas. There are 2 major forms of pancreatitis: acute (AP), which usually produces an episode of temporary illness, and chronic (CP), associated with severe pain, poor quality of life, and increased risk for the deadliest pancreatic cancer. Pancreatitis is the third most common reason for hospital admissions in those with GI disease and a heavy burden on the U.S. healthcare system Major AP responses include inappropriate/intra-acinar activation of digestive enzymes, increased serum level of amylase, neutrophil-driven inflammation, and acinar cell death. Key pathologic features of CP are loss of acinar tissue, chronic inflammation and fibrosis, ultimately leading to the loss of exocrine and endocrine pancreatic function. It is believed that CP results from repetitive subclinical or clinically evident bouts of AP. Excessive alcohol consumption is a major risk factor for both forms of pancreatitis; other key risk factors are smoking and age. The prevalence of these factors results in high pancreatitis incidence in Veterans as well as in military personnel. The pathogenesis of pancreatitis remains obscure and no effective treatment is available, primarily because we do not understand the underlying molecular and cellular mechanisms. Recent studies indicate that the lysosomal/autophagy pathways – a key catabolic mechanism by which cells eliminate damaged or defective cytoplasmic organelles and recycle their constituents for energy and biogenesis needs – are disrupted in pancreatitis. Our recent study revealed that these pathways are critical for maintaining cholesterol homeostasis in pancreas and their disordering results in acinar cell cholesterol overload. We further showed that the cholesterol-lowering drug simvastatin alleviated experimental pancreatitis. Taken together, these findings suggest that cholesterol metabolism is a clinically relevant modulator of pancreatitis severity. To validate the role of cholesterol dysregulation in driving pancreatitis and establish cholesterol synthesis pathway as a therapeutic target amenable to pharmacologic intervention in pancreatitis, we propose to examine the effects of cholesterol- lowering drugs with different action mechanism, simvastatin and bempedoic acid (BemA), on disease severity in several dissimilar mouse and ex-vivo (cellular) pancreatitis models. These preclinical AP and CP models reflect the spectrum of disease severity and etiologies, such as excessive alcohol consumption, gallstones, and ERCP. Statins came to medical use 30 years ago; BemA, which elicits fewer adverse effects than statins, was recently approved by FDA for lowering cholesterol. The proposed studies will examine the effects of these drugs on pancreatic cholesterol levels and disease severity using various regimens of drug administration in both preventive and therapeutic modes. The Specific Aims will determine the effects of simvastatin and BemA on pancreatitis parameters in preclinical models of AP (Aim 1) and CP (Aim 2) and changes in cholesterol levels in these models (Aim 3A); and compare simvastatin’s effects on ex-vivo pancreatitis responses in mouse versus human acinar cells (Aim 3B). If successful the study will provide information necessary to de-risk future clinical trials to validate the repurposing of simvastatin and/or BemA for pancreatitis treatment, and thus address the unmet clinical needs of Veterans. Comparative analysis of drugs’ effects in several preclinical pancreatitis models will allow us to select the best candidate(s) for clinical trials by excluding treatment regimens with toxic effects in the pancreas, insufficient cholesterol-lowering capacity, and/or little beneficial impact on pancreatitis responses. Repurposing FDA-approved drugs can significantly speed up and lower the cost of these trials. Thus, the proposed detailed study in preclinical models is a necessary prerequisite for clinical trials to assess the risks and benefits of our novel approach to address Veteran healthcare needs.

胰腺炎是一种常见的，可能致命的外分泌胰腺疾病。有两种主要形式 胰腺炎：急性（AP），通常会产生临时疾病的发作和慢性（CP） 严重疼痛，生活质量差以及最致命的胰腺癌风险增加。胰腺炎是 在患有胃肠道疾病的患者中入院的第三个最常见原因，美国的负担很大 医疗保健系统主要的AP反应包括消化酶的不适当/acinar激活， 淀粉酶，中性粒细胞驱动的注射和腺泡细胞死亡的血清水平升高。关键病理特征 CP的是腺泡组织，慢性感染和纤维化的丧失，最终导致外分泌和 内分泌胰腺功能。据认为，CP是由重复的亚临床或临床证据造成的 AP。饮酒过量是两种形式的胰腺炎的主要危险因素。其他关键风险因素 正在吸烟和年龄。这些因素的患病率也导致退伍军人的高胰腺炎入射 就像在军事人员中一样。 胰腺炎的发病机理仍然晦涩难懂，没有有效的治疗方法，主要是因为 我们不了解潜在的分子和细胞机制。最近的研究表明 溶酶体/自噬途径 - 细胞消除损伤或有缺陷的关键分解代谢机制 细胞质细胞器并回收其能量和生物发生需求的宪法 - 在 胰腺炎。我们最近的研究表明，这些途径对于维持胆固醇稳态至关重要 在胰腺及其无序导致腺泡细胞胆固醇过载导致。我们进一步表明 降低胆固醇的辛伐他汀减轻了实验性胰腺炎。总之，这些发现 表明胆固醇代谢是胰腺炎严重程度的临床相关调节剂。验证角色 在驱动胰腺炎中胆固醇失调并建立胆固醇合成途径作为一种疗法 我们建议对胰腺炎进行药物干预的靶标，我们建议检查胆固醇的作用 降低具有不同作用机制，辛伐他汀和be甲酸（BEMA）的药物对疾病严重程度的降低药物 几种不同的小鼠和前体（细胞）胰腺炎模型。这些临床前AP和CP模型反映了 疾病严重程度和病因的范围，例如过量的酒精消耗，胆结石和ERCP。 他汀类药物在30年前来医疗用途； Bema最近引起的不良影响比他汀类药物更少 经FDA批准降低胆固醇。 拟议的研究将检查这些药物对胰胆固醇水平和疾病的影响 在预防和治疗模式下使用药物给药各种方案的严重程度。具体 AIMS将确定辛伐他汀和BEMA对AP的临床前模型中胰腺炎参数的影响 （AIM 1）和CP（AIM 2）以及这些模型中胆固醇水平的变化（AIM 3A）；并比较辛伐他汀的 对小鼠与人类腺泡细胞中体内胰腺炎反应的影响（AIM 3B）。 如果成功，研究将提供必要的信息，以降低危险的未来临床试验以验证 重新利用辛伐他汀和/或BEMA进行胰腺炎治疗，因此可以满足未满足的临床需求 退伍军人。在几种临床前胰腺炎模型中对药物作用的比较分析将使我们能够选择 通过排除胰腺有毒作用的治疗方案，是临床试验的最佳候选者， 降低胆固醇的能力不足和/或对胰腺炎反应的有益影响很小。重新利用 FDA批准的药物可以显着加快和降低这些试验的成本。那，提议的详细 临床前模型中的研究是评估我们的风险和好处的临床试验的必要先决条件 满足资深医疗保健需求的新方法。