Genomics Strand

Project 2: Pathobiology of Nuclear Receptors

David J Mangelsdorf	David Moore
Department of Pharmacology, University of Texas Southwestern, Dallas, TX	Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
Ph.D: 1987, University of Arizona	Ph.D: 1979, University of Wisconsin
dmange@biochem.swmed.edu	moore@bcm.edu

Specific Aims

1. NR expression profiling from human patient samples with various metabolic diseases and cancer.

We will use QPCR to measure nuclear receptor (NR) and coregulator (CoR) mRNA expression in samples from patients with non-alcoholic steatosis hepatitis (NASH) and lung cancers.

2. NR expression profiling in mouse models of metabolic diseases and aging.

We plan to use both dietary and genetic approaches to assess the dynamics of NR expression relative to metabolic syndrome and aging. To this end, we will use our standardized QPCR assay to measure the mRNAs of tissues collected from wild-type and ob/ob mice treated with NR ligands, as well as C57/Bl6J mice over the course of aging.

3. Expression profiling of additional gene families that correlate to NR expression.

We will apply the same standardized QPCR profiling assays to measure the mRNA expression of NR coregulators, ATP-Binding Cassette transporters (ABCs), cytochrome p450s (p450s), and microRNAs (miRNAs). Samples harvested during the previous funding period and those acquired as part of Aims 1 and 2 will be interrogated.

4. Screen for functional interrelationships of NRs with adverse and idiosyncratic drug reactions.

In initial studies, expression of NRs, coregulators and drug metabolism targets would be profiled in wild type and humanized CAR and PXR mice in response to acetaminophen, troglitazone and diclofenac.  In later stages, these results would be compared to those with clinical samples
from patients with liver damage from the same hepatotoxic agents.