Regulation of hepatic stellate cells in development and alcoholic liver injury

摘要：这是一份申请K99/R00独立之路奖给尹春月博士的申请书，他是一名邮编。 加州大学旧金山分校博士生。殷博士正在确立自己作为一名年轻投资者的地位- Gator在酒精性肝病(ALD)的研究中。这项K99/R00奖将为殷博士提供支持 完成以下目标所必需的：1)获得肝星状细胞(HSC)和酒精的专业知识 肝脏损伤；2)开发研究斑马鱼HSC的新工具；3)开展独立研究 职业生涯。为了实现这些目标，殷博士组建了一个指导团队，由一位主要导师Dr。 加州大学旧金山分校生物化学和生物物理学教授Didier Stainier是斑马鱼肝脏方面的专家 发展，以及共同导师，加州大学旧金山分校医学教授Jacquelyn Maher博士 慢性肝损伤。 ALD是与酒精相关的发病率和死亡率的主要原因之一。HSC的激活是 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了解有限。尹医生的 长期目标是阐明HSC在酒精性肝损伤中的细胞反应。总的目标是 这一应用是为了了解肝星状细胞与邻近的肝窦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。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提案的目标：1) 了解SEC在HSC发育中的作用；2)确定HSC和SEC对急性急性白血病的反应。 3)了解急性酒精中毒后HSC-SEC相互作用的分子基础。 全肝损伤。在目标1中，她假设斑马鱼的HSC和SEC没有共同的前驱- 然而，SEC对于HSC的发展是必不可少的。她将通过血统追踪实验来验证这一假设 并通过在发育过程中操纵HSC和SEC之间的相互作用。在《目标2》中，尹博士将负责- 用时间推移活体成像实验表征HSC和SEC对急性酒精暴露的细胞反应 曼茨。在目标3中，她将进行基因图谱分析，以描述分子机制的不足- 观察HSC和SEC对急性酒精处理的反应。她还将测试血小板衍生的作用 生长因子在调节HSC-SEC相互作用中的作用这项拟议的研究具有创新性，因为它建立了- 建立了一个新的斑马鱼模型，用于研究酒精性肝损伤中HSC-SEC的相互作用。建议的重行- 搜索也具有重要意义，因为它是一系列研究的第一步，预计将阐明 肝星状细胞激活在酒精性肝损伤中的作用机制提出这项研究的理由是，一个COM- 对发育中的HSC和急性酒精暴露的全面描述将为 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.