BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10365153
• 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: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365153
• 关键词: Achievement; Acinar Cell; Age; Alcohol abuse; Alcoholic Pancreatitis; Alcohols; American; Automobile Driving; Autophagocytosis; Award; Bibliography; Biochemistry; Book Chapters; California; Cause of Death; Cell Death; Cells; Cellular Metabolic Process; Cholesterol; Cholesterol Homeostasis; Collaborations; Databases; Digestive System Disorders; Disease; Educational workshop; Endoplasmic Reticulum; Environmental Risk Factor; Enzymes; Excision; Exocrine pancreas; Functional disorder; Funding; Gastroenterology; Gastrointestinal Diseases; Genetic; Goals; Grant; Healthcare Systems; Hospitalization; Human; Impairment; Inflammation; Inflammatory; Inflammatory Response; Institution; Internet; Intervention; Journals; Knowledge; Link; Los Angeles; Lysosomes; Malignant neoplasm of pancreas; Manuscripts; Mediating; Medical Research; Medical center; Medicine; Mitochondria; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Alcohol Abuse and Alcoholism; Non-Malignant; Organelles; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Diseases; Pancreatitis; Paper; Participant; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patient Care; Peer Review; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Positioning Attribute; Program Research Project Grants; Proteins; Public Health; Publications; Publishing; Quality of life; Recommendation; Research; Resistance; Risk; Risk Factors; Role; SPINK1 gene; Science; Scientist; Severities; Signal Pathway; Signal Transduction; Site; Smoking; Survival Rate; Time; United States; United States National Institutes of Health; Universities; Veterans; Work; acute pancreatitis; base; care costs; career; chronic pancreatitis; cigarette smoke; clinical investigation; clinically relevant; drug development; editorial; effective therapy; endoplasmic reticulum stress; genetic approach; high risk; improved; indexing; insight; interest; medical schools; mitochondrial dysfunction; mitochondrial permeability transition pore; mortality; mouse model; necrotic tissue; novel; novel strategies; novel therapeutic intervention; patient population; professor; programs; residence; response; symposium; trafficking; translational approach; treatment strategy

Pancreatitis is a potentially fatal disease of exocrine pancreas, with significant morbidity and mortality, and a heavy burden on the US healthcare system. The disease is common in Veterans patient population. Its mechanism remains obscure, and no specific or effective treatment is available. Pancreatitis is not only associated with poor quality of life but is also a major risk factor for the deadly pancreatic cancer. The pancreatic acinar cell is a major participant in both acute and chronic pancreatitis. Its’ central physiologic function is to synthesize, transport, and secrete digestive enzymes. This is accomplished through coordinated actions of mitochondria, which provide energy (ATP); lysosomes and autophagy, mediating removal of damaged or dysfunctional organelles; and the endoplasmic reticulum (ER), a site of enzyme synthesis and folding. Several years ago we put forward a novel concept that Dysfunction of the pancreatic acinar cell organellar machinery mediating protein processing, trafficking, and degradation is central to the pathogenesis of acute pancreatitis. Our studies (as well as by other groups) have validated this hypothesis. These studies have been mostly performed within the framework of an NIH/NIDDK Program Project on which I serve as PD/PI – the first ever Program grant on pancreatitis, integrating the work of leading pancreatologists from 5 institutions across the US. We showed that both experimental and human pancreatitis are associated with profound disordering of acinar cell lysosomal, autophagy and mitochondrial pathways, and characterized the underlying mechanisms. We further showed that genetic and pharmacologic modulations of these pathways can ameliorate (or, conversely, cause) the disease. My current research provides further insight into these mechanisms. Studies supported by VA Merit award investigate the role of autophagy in chronic pancreatitis by using a novel, clinically relevant mouse model with pancreas-specific genetic insufficiency of the protein SPINK1 (mutations in which increase the risk of chronic pancreatitis in humans 20- to 40-fold). Studies supported by NIH/NIAAA and DOD investigate the role of organelle disorders in pancreatitis induced by environmental factors. The NIAAA-funded project examines the role of impaired lysosomal/autophagy pathway in the inflammatory response of alcoholic pancreatitis, and proposes new pharmacologic approaches. The DOD-funded project investigates the role of mitochondrial permeability transition pore (MPTP) in pancreatitis induced by combined action of alcohol and smoking, and analyzes the interrelations between mitochondrial dysfunction and ER stress. We apply pharmacologic and genetic approaches to examine beneficial effects of MPTP blockade in models of pancreatitis caused by alcohol and cigarette smoke. The focus of my most recent studies is on elucidating the mechanisms linking organellar disfunction to pancreatitis pathologies such as inflammation and cell death. We found, in particular, that lysosomal/autophagy dysfunction causes profound dysregulation of cholesterol metabolism in acinar cells, and that cholesterol-lowering drugs improve experimental pancreatitis. The findings are described in a manuscript now under revision in The Journal of Clinical Investigation; and I have submitted an R01 application to NIH to investigate the role of cholesterol dysregulation in the inflammatory and cell death responses of pancreatitis. Our studies have greatly advanced the knowledge of molecular mechanisms mediating pancreatitis, opened new research directions, and are recognized in the field as a paradigm shift.

胰腺炎是一种潜在的致命性外分泌胰腺疾病，其发病率和 死亡率，以及美国医疗体系的沉重负担。这种疾病在退伍军人中很常见 病人群体。其发病机制尚不清楚，目前尚无特效治疗方法。 可用。胰腺炎不仅与生活质量差有关，而且也是一个主要的危险因素。 致命的胰腺癌。胰腺腺泡细胞是两种急性胰腺炎的主要参与者。 和慢性胰腺炎。它的中心生理功能是合成、运输和分泌 消化酶。这是通过线粒体的协调行动来完成的，线粒体 提供能量(ATP)；溶酶体和自噬，介导受损或功能障碍的清除 细胞器；以及内质网(ER)，酶的合成和折叠的场所。 几年前，我们提出了一个新的概念，即胰腺腺泡功能障碍 调节蛋白质加工、运输和降解的细胞器机制是 在急性胰腺炎的发病机制中处于中心地位。我们的研究(以及其他小组的研究) 已经证实了这一假设。这些研究大多是在以下框架内进行的 我担任PD/PI的NIH/NIDDK计划项目--有史以来第一个计划拨款 胰腺炎，整合了来自全美5个机构的领先胰腺病学家的工作。 我们发现实验性和人类胰腺炎都与严重的 腺泡细胞溶酶体、自噬和线粒体通路紊乱 潜在的机制。我们进一步表明，遗传和药物调节 这些途径可以改善(或者相反，导致)疾病。 我目前的研究为这些机制提供了更深入的见解。退伍军人事务部资助的研究 优秀奖通过一种新的临床应用研究自噬在慢性胰腺炎中的作用 胰腺特异性SPINK1蛋白基因缺陷相关小鼠模型 (突变使人类患慢性胰腺炎的风险增加20-40倍)。研究 在NIH/NIAAA和美国国防部的支持下，研究细胞器紊乱在胰腺炎中的作用 由环境因素引起的。NIAAA资助的项目考察了受损者的作用 溶酶体/自噬途径在酒精性胰腺炎炎症反应中的作用 提出了新的药理学方法。国防部资助的项目调查了 急性胰腺炎时线粒体通透性转换孔(MPTP)的变化 酒精和吸烟，并分析线粒体功能障碍与ER的相互关系 压力。我们应用药理学和遗传学方法来检查MPTP的有益效果。 对酒精和香烟烟雾所致胰腺炎模型的阻断。我最关注的焦点 最近的研究是阐明细胞器功能障碍与胰腺炎之间的联系机制。 炎症和细胞死亡等病理现象。我们特别发现， 溶酶体/自噬功能障碍导致严重的胆固醇代谢失调 腺泡细胞，以及降胆固醇药物改善实验性胰腺炎。调查结果 在《临床调查杂志》上正在修改的一篇手稿中有描述；我 已经向NIH提交了R01申请，以调查胆固醇失调在 胰腺炎的炎症反应和细胞死亡反应。 我们的研究极大地促进了对分子机制的了解 开辟了新的研究方向，并被该领域公认为范式的转变。