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BLR&D Research Career Scientist Award

BLR

基本信息

批准号：
10047244
负责人：
Carol A. Casey
金额：
--
依托单位：
OMAHA VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-10-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10047244
关键词：
Address Admission activity Affect Alcohol abuse Alcoholic Fatty Liver Alcoholic Liver Diseases Alcohols American Animal Model Apoptotic Area Asialoglycoprotein Receptor Autophagocytosis Autophagosome Award Basic Science Biochemical Biology Book Chapters Carcinoembryonic Antigen Cells Cellular biology Cessation of life Chronic Clinical Collaborations Country Cytolysis Data Defect Destinations Development Disease Progression Endocytosis Ensure Ethanol Ethanol Metabolism Exocytosis Family Fatty Liver Fibronectins Functional disorder General Population Goals Golgi Apparatus Grant Review Guanosine Triphosphate Phosphohydrolases Healthcare Heavy Drinking Hepatic Hepatocyte Hepatotoxicity Impairment In Vitro Incidence Inflammatory Response Injury Investigation Journals Knowledge Laboratories Lead Ligands Link Lipids Liver Liver Carbohydrate-Binding Protein Liver diseases Manuscripts Mediating Medical Medical center Membrane Mentors Military Personnel Mission Monitor Monomeric GTP-Binding Proteins Morphology National Institute on Alcohol Abuse and Alcoholism Organelles Pathogenesis Pathway interactions Patients Peer Review Physiological Play Process Program Development Protein Secretion Proteins Publishing Recycling Research Research Personnel Role Scientist Seminal Signal Transduction Societies Therapeutic Therapeutic Intervention Time Toxic effect Toxin Training United States National Institutes of Health Vesicle Veterans Work World Health alcohol consequences alcohol effect alcohol exposure base career chronic liver disease design experimental study improved in vivo insight liver injury liver transplantation member military veteran non-alcoholic non-alcoholic fatty liver disease novel population health problem drinker programs protein transport receptor receptor mediated endocytosis receptor recycling special interest group symposium therapeutic development therapeutic target therapeutically effective therapy development trafficking trans-Golgi Network undergraduate student uptake

项目摘要

The goal of my current work is to examine how ethanol exposure results in impaired function of the Golgi apparatus. The Golgi apparatus (also called the Golgi body or Golgi complex) packages proteins into membrane bound vesicles inside the cell before the vesicles are sent to their destination. As such, this organelle resides at the intersection of the secretory, lysosomal, and endocytic pathways; it is known to be of particular importance in processing proteins for secretion. Previous work from our laboratory has identified multiple defects in endocytosis, protein trafficking, and secretion, after alcohol administration, but we have not until now, examined a role for altered Golgi function in these processes. Because the incidence of alcoholic liver disease is greater in the Veteran population and more than half of all medical admissions in VA Medical Centers across the country are linked to alcohol abuse, we are focusing efforts towards the identification of potential targets to intervene during the progressive injury which occurs after chronic alcohol administration, and perhaps the Golgi will prove to be such a target. Of central importance to our study is the role of a small GTPase, Rab3D, which is involved in exocytosis, secretion and vesicle trafficking. We have shown that Rab3D protein content was significantly decreased after alcohol administration, and recently we have obtained exciting new preliminary data that ethanol- impaired Rab3D function plays an important role in Golgi disorganization and fragmentation. The studies proposed in this application will extend our ongoing investigation of how ethanol alters hepatocyte biology, specifically in protein processing, to an examination of its role in transport through the Golgi. We provide a concept as to how alcohol-induced remodeling of Golgi morphology is a significant impairment of post-Golgi trafficking, and this leads to utilization of trans-Golgi membranes for the formation of autophagosomes. For this work, we present the following hypothesis: Ethanol exposure contributes to Golgi disorganization via its fragmentation and autophagy-mediated Golgi membrane lysis, leading to impaired endocytic and exocytic protein trafficking. Altered distribution and function of the small GTPase Rab3D plays a critical role in these alterations. To examine our hypothesis, we have proposed three specific aims; in Aim 1 we will characterize the distribution of Rab3D in vitro and in vivo in liver cells before and after EtOH administration. Studies proposed for Aim 2 will establish a role for Rab3D in the transport of physiologically relevant hepatic proteins. These studies will be followed by experiments proposed for Aim 3 where we will determine if EtOH- induced Golgi disorganization and fragmentation contribute to autophagosome formation and how altered Rab3D function affects hepatocyte autophagy. Altogether, successful completion of these aims will characterize the effect of EtOH on Golgi disorganization, and establish a role for altered Rab3D during this process. We will be able to correlate mechanisms of alcohol-mediated liver cell trafficking impairments with impaired Golgi function and provide key information that could lead to therapeutic strategies aimed at reducing or eliminating liver injury. In this work, I am joined by three outstanding co-investigators (Drs. Petrosyan, Thomes and Rasineni), the latter two are young investigators based at the Omaha VA. I also have collaborative effort with multiple VA investigators, as outlined in my research plan, and these collaborations have been highly productive. The exploration of how alcohol impairs function of important organelles such as the Golgi and lipid droplets will provide new avenues for the development of therapeutic interventions for both alcoholic and non-alcoholic fatty liver disease. Our contribution is significant since this is a critical step to provide translational knowledge for the development of therapies for fatty liver disease. Additionally, our findings will also have broader implications for other hepatic diseases characterized by hepatic injury. With the expertise and collaborations available to my group, we anticipate that we will be successful in these studies and will be able to contribute to improved healthcare for Veteran patients by the identification of mechanisms involved in the alcoholic liver injury.

我目前的工作目标是研究乙醇暴露如何导致高尔基体功能受损