Grants and Contracts Details
Description
We have had a long-standing interest in the zonal control of gene expression in the adult liver. This
phenomenon, whereby specific genes are expressed in pericentral hepatocytes and other genes are
expressed in periportal hepatocytes, allows the liver to compartmentalize different metabolic functions in
distinct regions. Using mouse models, we previously characterized defined enhancer elements that confer
zonal expression to linked transgenes. We also demonstrated that the beta-catenin signaling pathway is
important for activity of pericentral enhancers. During the last funding period of this grant, we made the
novel observation that the retinoic acid related orphan receptor alpha (RORA) is important for pericentral
gene regulation. The goal of this competitive renewal is to use mouse models and high throughput
sequencing to explore further the role of RORA in zonal gene regulation in the mouse liver. This will be
accomplished by the following aims:
Aim 1: Analysis of direct and indirect targets of RORA in pericentral gene expression. Pericentral and
periportal hepatocytes will be purified from our unique transgenic mouse line and performing RNA-Seq and
ChIP-Seq with antibodies against RORA and related factors as well as modified chromatin marks.
Aim 2. Identify additional enhancers that exhibit pericentral or periportal activity using a novel Adenoassociated
virus (AAV) system developed in our lab.
Aim 3: Determine whether RORA is important for the homeostatic stem cell properties of pericentral
hepatocytes by Cre-recombinase mediated cell lineage tracing.
Aim 4: Determine whether RORA is important for liver regeneration using the well established carbon
tetrachloride model of liver injury.
Status | Finished |
---|---|
Effective start/end date | 9/1/07 → 6/30/23 |
Funding
- National Institute Diabetes & Digestive & Kidney: $1,377,000.00
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