BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

基本信息

批准号：
10512760
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
项目类别：
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/10512760
关键词：
Achievement Acinar Cell 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 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 United States United States National Institutes of Health Universities Veterans Work acute pancreatitis care costs career chronic pancreatitis cigarette smoke clinical investigation clinically relevant drug development editorial effective therapy endoplasmic reticulum stress genetic approach high risk human old age (65+)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 pharmacologic professor programs residence response symposium trafficking translational approach treatment strategy

项目摘要

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.

胰腺炎是一种潜在致命的胰腺外分泌疾病，具有显着的发病率和这种疾病在退伍军人中很常见。其机制仍不清楚，并且没有具体或有效的治疗方法。胰腺炎不仅与生活质量差有关，而且还是一个主要的危险因素。胰腺腺泡细胞是致命的胰腺癌的主要参与者。其主要生理功能是合成、运输和分泌。这是通过线粒体的协调作用来完成的。提供能量（ATP）和自噬，介导去除受损或功能失调的物质；细胞器；以及内质网（ER），酶合成和折叠的场所。几年前我们提出了一个新的概念：胰腺腺泡功能障碍介导蛋白质加工、运输和降解的细胞器机器是我们的研究（以及其他小组的研究）是急性胰腺炎发病机制的核心。这些研究大多是在该框架内进行的。我担任 NIH/NIDDK 项目的 PD/PI——有史以来的第一个项目拨款胰腺炎，整合了来自美国 5 个机构的顶尖胰腺学家的工作。我们表明，实验性胰腺炎和人类胰腺炎都与严重的胰腺炎相关。腺泡细胞溶酶体、自噬和线粒体途径的紊乱，并进行了表征我们进一步表明了遗传和药理调节。这些途径可以改善（或者相反，导致）疾病。我目前的研究进一步深入了解了 VA 支持的这些机制。优异奖通过使用一种新型的临床研究自噬在慢性胰腺炎中的作用具有胰腺特异性 SPINK1 蛋白遗传缺陷的相关小鼠模型（突变会使人类患慢性胰腺炎的风险增加 20 至 40 倍）。由 NIH/NIAAA 和 DOD 支持调查细胞器紊乱在胰腺炎中的作用 NIAAA 资助的项目研究了受损者的作用。酒精性胰腺炎炎症反应中的溶酶体/自噬途径，以及提出了新的药理学方法，由国防部资助的项目研究了其作用。线粒体通透性转换孔（MPTP）在联合作用诱导的胰腺炎中的作用酒精和吸烟，以及线粒体功能障碍和 ER 之间的相互关系我们应用药理学和遗传学方法来检查 MPTP 的有益作用。由酒精和香烟烟雾引起的胰腺炎模型的封锁是我最关注的焦点。最近的研究旨在阐明细胞器功能障碍与胰腺炎之间的联系机制我们特别发现，例如炎症和细胞死亡。溶酶体/自噬功能障碍导致胆固醇代谢的严重失调腺泡细胞，降胆固醇药物可以改善实验性胰腺炎。《临床研究杂志》和《我》正在修订的手稿中对此进行了描述；已向 NIH 提交了 R01 申请，以研究胆固醇失调在胰腺炎的炎症和细胞死亡反应。我们的研究极大地推进了介导分子机制的知识胰腺炎开辟了新的研究方向，并在该领域被认为是一种范式转变。