Regulation of hepatic stellate cells in development and alcoholic liver injury

肝星状细胞发育和酒精性肝损伤的调控

基本信息

批准号：
8788863
负责人：
Chunyue Yin
金额：
$ 24.9万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788863
关键词：
Acute Affect Alcohol abuse Alcohol consumption Alcoholic Liver Diseases Alcohols Animal Model Animals Award Behavior Biochemistry Biophysics California Cell Communication Cell Lineage Cell Proliferation Cells Cellular Morphology Cellular biology Chronic Cicatrix Data Deposition Development Documentation Embryo Endothelial Cells Event Extracellular Matrix Genes Goals Hepatic Stellate Cell Human Image Image Analysis In Vitro Injury Knowledge Lead Life Liver Liver Fibrosis Medicine Mentors Mission Modeling Molecular Morbidity - disease rate Myofibroblast National Institute on Alcohol Abuse and Alcoholism Outcome Paracrine Communication Pathway interactions Phase Platelet-Derived Growth Factor Population Postdoctoral Fellow Prevention Public Health Regulation Reporter Research Research Personnel Role San Francisco Signal Transduction Study models Testing Therapeutic Time Tissues Transgenic Organisms Translating United States Universities Vitamin A Work Yin Zebrafish abstracting alcohol abuse therapy alcohol effect alcohol exposure alcohol response base burden of illness career cell behavior cell motility design disability improved in vivo innovation insight liver injury mortality mutant novel problem drinker professor public health relevance research study response tool

项目摘要

Abstract: This is an application for the K99/R00 Pathway to Independence Award for Dr. Chunyue Yin, a post- doctoral fellow at the University of California, San Francisco. Dr. Yin is establishing herself as a young investi- gator in the research of alcoholic liver disease (ALD). This K99/R00 award will provide Dr. Yin with the support necessary to accomplish the following goals: 1) to gain expertise in hepatic stellate cells (HSC) and alcoholic liver injury; 2) to develop new tools for studying HSC in zebrafish; and 3) to develop an independent research career. To achieve these goals, Dr. Yin has assembled a mentoring team comprised of a primary mentor, Dr. Didier Stainier, Professor of Biochemistry and Biophysics at UCSF, who is an expert in zebrafish liver development, and a co-mentor, Dr. Jacquelyn Maher, Professor of Medicine at UCSF, who is an expert in al- coholic liver injury. ALD is one of the leading causes of alcohol-related morbidity and mortality. Activation of HSC is the key event in ALD, but our understanding of the regulation of HSC in alcoholic liver injury is limited. Dr. Yin's long-term goal is to elucidate the cellular responses of HSC in alcoholic liver injury. The overall objective of this application is to understand the interactions between HSC and neighboring sinusoidal endothelial cells (SEC) in liver development and acute alcoholic injury by using the zebrafish model. The central hypothesis is that paracrine signals between HSC and SEC are required for HSC development and regulate their behaviors in response to alcohol. Dr. Yin will achieve the objective of the proposal by pursuing three specific aims: 1) Understand the roles of SEC in HSC development; 2) Determine the responses of HSC and SEC to acute al- coholic liver injury; and 3) Understand the molecular basis of HSC-SEC interactions in response to acute alco- holic liver injury. In Aim 1, she hypothesizes that in zebrafish HSC and SEC do not share a common precur- sor, yet SEC are essential for HSC development. She will test this hypothesis by lineage-tracing experiments and by manipulating the interactions between HSC and SEC during development. In Aim 2, Dr. Yin will char- acterize the cellular responses of HSC and SEC to acute alcohol exposure by time-lapse live imaging experi- ments. In Aim 3, she will perform gene-profiling analyses to characterize the molecular mechanisms underly- ing the responses of HSC and SEC to acute alcohol treatment. She will also test the role of Platelet-Derived Growth Factor in regulating HSC-SEC interactions. The proposed research is innovative because it estab- lishes a novel zebrafish model for studying HSC-SEC interactions in alcoholic liver injury. The proposed re- search is also significant because it is the first step in a continuum of research that is expected to elucidate the mechanisms of HSC activation in alcoholic liver injury. The rationale for the proposed research is that a com- prehensive characterization of HSC in development and acute alcohol exposure will provide novel insights into our understanding of HSC in ALD, and may translate into new targets for therapy.

摘要：这是后博士尹春月博士申请 K99/R00 独立之路奖的申请。加州大学旧金山分校博士研究员。尹博士正在将自己打造成一名年轻的研究人员鳄鱼在酒精性肝病（ALD）的研究中。此次K99/R00奖项将为尹博士提供支持实现以下目标所必需的：1）获得肝星状细胞（HSC）和酒精方面的专业知识肝损伤； 2）开发研究斑马鱼HSC的新工具； 3）开展独立研究职业。为了实现这些目标，尹博士组建了一个由主要导师，博士组成的指导团队。 Didier Stainier，加州大学旧金山分校生物化学和生物物理学教授，斑马鱼肝脏专家共同导师 Jacquelyn Maher 博士是加州大学旧金山分校的医学教授，他是以下领域的专家：酒精性肝损伤。 ALD 是酒精相关发病和死亡的主要原因之一。 HSC 的激活是 HSC 是 ALD 中的关键事件，但我们对 HSC 在酒精性肝损伤中的调节作用的了解有限。尹博士的长期目标是阐明 HSC 在酒精性肝损伤中的细胞反应。总体目标该应用是为了了解 HSC 和邻近的肝窦内皮细胞之间的相互作用 (SEC) 使用斑马鱼模型研究肝脏发育和急性酒精损伤。中心假设是 HSC 和 SEC 之间的旁分泌信号是 HSC 发育和调节其行为所必需的对酒精的反应。尹博士将通过追求三个具体目标来实现该提案的目标：1) 了解 SEC 在 HSC 发展中的作用； 2) 确定 HSC 和 SEC 对急性酒精的反应酒精性肝损伤； 3) 了解 HSC-SEC 相互作用响应急性酒精的分子基础肝损伤。在目标 1 中，她假设斑马鱼 HSC 和 SEC 不具有共同的前体。不错，但 SEC 对于 HSC 的发展至关重要。她将通过谱系追踪实验来检验这个假设以及在开发过程中操纵 HSC 和 SEC 之间的相互作用。在目标 2 中，尹博士将介绍—— 通过延时实时成像实验表征 HSC 和 SEC 对急性酒精暴露的细胞反应评论。在目标 3 中，她将进行基因谱分析，以表征潜在的分子机制： HSC 和 SEC 对急性酒精治疗的反应。她还将测试血小板衍生的作用调节 HSC-SEC 相互作用的生长因子。拟议的研究具有创新性，因为它建立了提出了一种新的斑马鱼模型，用于研究酒精性肝损伤中 HSC-SEC 相互作用。建议重新搜索也很重要，因为它是连续研究的第一步，预计将阐明酒精性肝损伤中 HSC 激活的机制。拟议研究的基本原理是， HSC 发育过程和急性酒精暴露的全面表征将为以下方面提供新的见解我们对 HSC 在 ALD 中的理解，并可能转化为新的治疗靶点。