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BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

基本信息

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
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/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

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.

胰腺炎是一种潜在的致死性外分泌胰腺疾病，具有显著的发病率和发病率