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.
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.
|Tsedensodnom, Orkhontuya; Vacaru, Ana M; Howarth, Deanna L et al. (2013) Ethanol metabolism and oxidative stress are required for unfolded protein response activation and steatosis in zebrafish with alcoholic liver disease. Dis Model Mech 6:1213-26|
|Yin, Chunyue; Evason, Kimberley J; Asahina, Kinji et al. (2013) Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Invest 123:1902-10|
|Hochgreb-Hagele, Tatiana; Yin, Chunyue; Koo, Daniel E S et al. (2013) Laminin *1a controls distinct steps during the establishment of digestive organ laterality. Development 140:2734-45|
|Howarth, Deanna L; Yin, Chunyue; Yeh, Karen et al. (2013) Defining hepatic dysfunction parameters in two models of fatty liver disease in zebrafish larvae. Zebrafish 10:199-210|
|Yin, Chunyue; Evason, Kimberley J; Maher, Jacquelyn J et al. (2012) The basic helix-loop-helix transcription factor, heart and neural crest derivatives expressed transcript 2, marks hepatic stellate cells in zebrafish: analysis of stellate cell entry into the developing liver. Hepatology 56:1958-70|