Regulation of hepatic stellate cells in development and alcoholic liver injury

翻译后摘要：这是一个应用程序的K99/R 00路径到独立奖博士尹春跃，后， 加州大学旧金山分校弗朗西斯科博士研究员。尹博士正在建立自己作为一个年轻的投资- 在酒精性肝病（ALD）的研究中，K99/R 00项目将为尹博士提供 必须完成以下目标：1）获得肝星状细胞（HSC）和酒精的专业知识 肝损伤; 2）开发研究斑马鱼HSC的新工具; 3）开展独立研究 事业为了实现这些目标，尹博士组建了一个指导团队，由一位主要的导师， 迪迪埃·卡尼尔，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 发展，和共同导师，杰奎琳马赫博士，医学教授在加州大学旧金山分校，谁是在铝专家， 酒精性肝损伤 ALD是酒精相关发病率和死亡率的主要原因之一。HSC的激活是 HSC是ALD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。尹医生的 长期目标是阐明酒精性肝损伤中HSC的细胞反应。的总体目标 本申请旨在了解HSC与邻近的窦状隙内皮细胞之间的相互作用 (SEC)在肝脏发育和急性酒精损伤中的作用。核心假设是 HSC和SEC之间的旁分泌信号是HSC发育和调控其行为所必需的 对酒精的反应。尹博士将通过以下三个具体目标来实现建议的目标： 了解SEC在HSC发育中的作用; 2）确定HSC和SEC对急性AL-1的反应。 酒精性肝损伤; 3）理解急性酒精性肝损伤后HSC-SEC相互作用的分子基础。 霍利奇肝损伤。在目标1中，她假设在斑马鱼中HSC和SEC没有共同的前体， 然而，SEC对于HSC发展是必不可少的。她将通过血统追踪实验来验证这一假设 以及在发育过程中操纵HSC和SEC之间的相互作用。在目标2中，尹博士将负责- 通过实时成像实验观察HSC和SEC对急性酒精暴露的细胞反应， 的部分。在目标3中，她将进行基因谱分析，以表征潜在的分子机制- 观察HSC和SEC对急性酒精治疗的反应。她还将测试血小板衍生的 生长因子调节HSC-SEC相互作用。这项研究是创新的，因为它建立了- 为研究酒精性肝损伤中HSC与SEC的相互作用提供了一种新的斑马鱼模型。拟议的重新- 搜索也很重要，因为它是一系列研究的第一步，这些研究有望阐明 酒精性肝损伤中HSC活化的机制这项研究的基本原理是，一个共同的， 对HSC发育和急性酒精暴露的深入研究将为以下方面提供新的见解： 我们对ALD中HSC的理解，并可能转化为新的治疗靶点。

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.