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

• 批准号: 8164707
• 负责人: Chunyue Yin
• 金额: $ 9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8164707
• 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; 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; mortality; mutant; novel; problem drinker; professor; research study; response; tool

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because a thorough understanding of hepatic stellate cell biology will enable us to develop tools to modulate their activation, which may potentially lead to prevention or reversion of alcoholic liver disease. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to extend healthy life and reduce the burdens of illness and disability.

描述（由申请人提供）：这是加州大学旧金山分校博士后尹纯月博士申请 K99/R00 独立之路奖的申请。尹博士正在将自己定位为酒精性肝病（ALD）研究领域的年轻研究者。该K99/R00奖项将为尹博士提供实现以下目标所需的支持：1）获得肝星状细胞（HSC）和酒精性肝损伤方面的专业知识； 2）开发研究斑马鱼HSC的新工具； 3）发展独立的研究事业。为了实现这些目标，尹博士组建了一个导师团队，由主要导师、斑马鱼肝脏发育专家、加州大学旧金山分校生物化学和生物物理学教授 Didier Stainier 博士和共同导师 Jacquelyn 博士组成。 Maher，加州大学旧金山分校医学教授，酒精性肝损伤方面的专家。 ALD 是酒精相关发病和死亡的主要原因之一。 HSC的激活是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。尹博士的长期目标是阐明HSC在酒精性肝损伤中的细胞反应。本应用的总体目标是通过使用斑马鱼模型了解 HSC 与邻近的正弦内皮细胞 (SEC) 在肝脏发育和急性酒精损伤中的相互作用。中心假设是 HSC 和 SEC 之间的旁分泌信号是 HSC 发育所必需的，并调节它们对酒精的反应行为。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对急性酒精性肝损伤的反应； 3) 了解 HSC-SEC 相互作用响应急性酒精性肝损伤的分子基础。在目标 1 中，她假设斑马鱼的 HSC 和 SEC 不具有共同的前体，但 SEC 对于 HSC 的发育至关重要。她将通过谱系追踪实验以及在发育过程中操纵 HSC 和 SEC 之间的相互作用来检验这一假设。在目标 2 中，Yin 博士将通过延时实时成像实验来表征 HSC 和 SEC 对急性酒精暴露的细胞反应。在目标 3 中，她将进行基因谱分析，以表征 HSC 和 SEC 对急性酒精治疗反应的分子机制。她还将测试血小板衍生生长因子在调节 HSC-SEC 相互作用中的作用。这项研究具有创新性，因为它建立了一种新的斑马鱼模型来研究酒精性肝损伤中 HSC-SEC 的相互作用。拟议的研究也很重要，因为它是一系列研究的第一步，有望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 发育和急性酒精暴露的全面特征将为我们对 ALD 中 HSC 的理解提供新的见解，并可能转化为新的治疗目标。 公共健康相关性：拟议的研究与公共健康相关，因为对肝星状细胞生物学的透彻了解将使我们能够开发出调节其激活的工具，这可能有助于预防或逆转酒精性肝病。因此，拟议的研究与 NIH 使命的一部分相关，即发展有助于延长健康寿命并减轻疾病和残疾负担的基础知识。