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）：这是加利福尼亚大学旧金山分校的博士后研究员Chunyue Yin博士的K99/R00途径独立奖的申请。 Yin博士正在建立自己是酗酒肝病研究（ALD）研究的年轻投资。该K99/R00奖将为Yin博士提供实现以下目标所需的支持：1）获得肝星细胞（HSC）和酒精性肝损伤的专业知识； 2）开发用于研究斑马鱼中HSC的新工具； 3）发展独立的研究职业。为了实现这些目标，Yin博士组建了一个由主要导师组成的指导团队，Didier Stainier博士是UCSF的生物化学和生物物理学教授，他是斑马鱼肝脏发展专家，同事的专家，同事，UCSF医学博士Jacquelyn Maher博士，UCSF，UCSF，UCSF，AL-COHIOL-COHIOL-COHIOL-COHIOL INFIFCOR INFERICH-COHIOL INFIFF。 ALD是与酒精有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，但是我们对酒精性肝损伤中HSC调节的理解是有限的。 Yin博士的长期目标是阐明酒精肝损伤中HSC的细胞反应。该应用的总体目的是通过使用斑马鱼模型来了解肝发育和急性酒精损伤中HSC与邻近正弦内皮细胞（SEC）之间的相互作用。中心假设是HSC开发需要HSC和SEC之间的旁分泌信号，并根据酒精的响应调节其行为。 Yin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开发中的作用； 2）确定HSC和SEC对急性神经抗性肝损伤的反应； 3）理解响应急性藻类肝损伤的HSC-SEC相互作用的分子基础。在AIM 1中，她假设在斑马鱼中，HSC和SEC并不具有共同的precur-sor，但SEC对于HSC开发至关重要。她将通过谱系追踪实验以及在开发过程中操纵HSC与SEC之间的相互作用来检验这一假设。在AIM 2中，Yin博士将通过延时活成像体验来征收HSC和SEC对急性酒精暴露的细胞反应。在AIM 3中，她将执行基因促进分析，以表征HSC和SEC对急性酒精治疗的反应的分子机制。她还将测试血小板衍生的生长因子在调节HSC-SEC相互作用中的作用。拟议的研究具有创新性，因为它构成了一种新型斑马鱼模型，用于研究酒精性肝损伤中HSC-SEC相互作用。提出的调查也很重要，因为它是一项连续研究的第一步，该研究有望阐明酒精肝损伤中HSC激活的机制。拟议的研究的理由是，在发育和急性酒精暴露中，HSC对HSC的综合表征将为我们对ALD中HSC的理解提供新的见解，并可能转化为新的治疗目标。 公共卫生相关性：拟议的研究与公共卫生有关，因为对肝星细胞生物学的透彻了解将使我们能够开发工具来调节其激活，这可能会导致预防或逆转酒精性肝病。因此，拟议的研究与NIH使命的一部分有关，该任务与发展基本知识有关，这将有助于延长健康的生活并减轻疾病和残疾的负担。