Metabolic regulation of pancreatitis

胰腺炎的代谢调节

• 批准号: 10559568
• 负责人: Rodger A. Liddle
• 金额: $ 36.23万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559568
• 关键词: Acinar Cell; Acinus organ component; Adenosine Triphosphate; Affect; Alcohol consumption; Alcoholic Pancreatitis; Alcohols; Animal Model; Animals; Caerulein; Calcium; Cells; Clinical; Clinical Trials; Cytoplasm; Data; Development; Diet; Disease; Enzyme Activation; Esters; Ethanol; Exocrine pancreas; Experimental Models; Fatty Acids; Health; Human; Hypophosphatemia; Impairment; In Vitro; Injury; Investigation; Mediating; Metabolic; Mitochondria; Modeling; Multiple Organ Failure; Mus; Organ; Organelles; Pancreas; Pancreatic Injury; Pancreatic duct; Pancreatitis; Pathogenesis; Patients; Persons; Prevention; Production; Protein Biosynthesis; Regulation; Risk Factors; Role; Serum; Severities; Severity of illness; Study models; Supplementation; Testing; Translating; United States; absorption; acute pancreatitis; alcohol effect; alcohol induced pancreatic injury; alcohol prevention; cell injury; chronic pancreatitis; design; dietary; effective therapy; feeding; human disease; improved; inorganic phosphate; mitochondrial dysfunction; mortality; mouse model; novel; pre-clinical; premature; pressure; prevent; problem drinker; protective effect; restoration

Abstract Acute pancreatitis is a debilitating disease that affects more than 280,000 people in the United States. A hallmark of acute pancreatitis is systemic injury and multi-organ failure leading to mortality in 3-20% of patients. There are currently no treatments for acute pancreatitis. Alcohol consumption is a major cause of human acute pancreatitis and despite intensive investigation the pathogenesis of alcohol-induced pancreatitis remains poorly understood. Evidence suggests that acinar cell injury is associated with mitochondrial dysfunction leading to ATP depletion and prevention of mitochondrial damage or restoration of mitochondrial function may limit pancreatitis. Phosphate availability is required for ATP synthesis. Clinical hypophosphatemia is common in alcoholic patients and alcohol itself impairs dietary phosphate absorption. In preliminary studies, we discovered that reduced serum phosphate levels in patients with acute pancreatitis are associated with increased pancreatitis severity. We proposed that reduced phosphate availability may predispose to alcohol-induced pancreatic injury and may be central to the development of alcoholic pancreatitis. Our preliminary data indicate that alcohol rapidly induces pancreatitis when mice are fed a low phosphate diet, consistent with the concept that hypophosphatemia sensitizes the pancreas to alcohol. The current study is designed to test the hypothesis that alcohol-induced pancreatitis can be ameliorated by phosphate administration. We will determine the contribution of hypophosphatemia to pancreatitis severity, the protective effects of phosphate treatment in mouse models of pancreatitis, and the mechanisms underlying the effects of hypophosphatemia on pancreatic injury. Successful completion of these studies will yield compelling pre-clinical data for a novel, simple and effective treatment for pancreatitis that will provide the basis for a clinical trial in humans.

摘要 急性胰腺炎是一种使人衰弱的疾病，在美国影响超过28万人。一 急性胰腺炎的标志是全身性损伤和多器官衰竭，导致3-20%的患者死亡。 患者目前还没有治疗急性胰腺炎的方法。酒精消费是导致 人急性胰腺炎，尽管深入研究酒精诱导的胰腺炎的发病机制， 仍然知之甚少。有证据表明，腺泡细胞损伤与线粒体 导致ATP耗竭的功能障碍和防止线粒体损伤或恢复线粒体 功能可以限制胰腺炎。磷酸盐的可用性是ATP合成所必需的。临床 低磷酸盐血症在酗酒患者中很常见，并且酒精本身会损害饮食中磷酸盐的吸收。在 初步研究发现，急性胰腺炎患者血清磷酸盐水平降低， 与胰腺炎严重程度增加相关。我们认为，减少磷酸盐的可用性， 易受酒精诱导的胰腺损伤，可能是酒精性胰腺炎发生的中心因素。 胰腺炎我们的初步数据表明，当小鼠被喂食低浓度的酒精时， 磷酸盐饮食，与低磷酸盐血症使胰腺对酒精敏感的概念一致。的 目前的研究旨在验证酒精诱导的胰腺炎可以通过 磷酸盐给药。我们将确定低磷血症对胰腺炎严重程度的影响， 磷酸盐治疗对胰腺炎小鼠模型的保护作用，以及磷酸盐治疗的机制。 低磷血症对胰腺损伤的影响成功完成这些研究将产生令人信服的 一种新型、简单、有效的胰腺炎治疗方法的临床前数据，将为 人体临床试验

项目成果

Pressure-sensing Piezo1: the eyes have it.

• DOI: 10.1113/jp281122
• 发表时间: 2021-01
• 期刊: The Journal of physiology
• 作者: Swain SM;Liddle RA
• 通讯作者: Liddle RA

Hypophosphatemia as a Predictor of Clinical Outcomes in Acute Pancreatitis: A Retrospective Study.

低磷血症作为急性胰腺炎临床结果的预测因子：一项回顾性研究。

• DOI: 10.1097/mpa.0000000000002265
• 发表时间: 2024
• 期刊: Pancreas
• 影响因子: 2.9
• 作者: Lee,JoshuaP;Darlington,Kimberly;Henson,JacquelineB;Kothari,Darshan;Niedzwiecki,Donna;Farooq,Ahmad;Liddle,RodgerA
• 通讯作者: Liddle,RodgerA

Mechanosensing Piezo channels in gastrointestinal disorders.

• DOI: 10.1172/jci171955
• 发表时间: 2023-10-02
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Swain, Sandip M.;Liddle, Rodger A.
• 通讯作者: Liddle, Rodger A.

Calcium in Pancreatitis … Immune Cells, Too?

• DOI: 10.1093/function/zqaa030
• 发表时间: 2021
• 期刊: Function (Oxford, England)
• 作者: Vigna SR;Liddle RA
• 通讯作者: Liddle RA

Piezo1 acts upstream of TRPV4 to induce pathological changes in endothelial cells due to shear stress.

• DOI: 10.1074/jbc.ra120.015059
• 发表时间: 2021-01
• 期刊: The Journal of biological chemistry
• 作者: Swain SM;Liddle RA
• 通讯作者: Liddle RA