Investigators:
Thomas
Cappola, MD, ScM (PI), Sridhar Hannenhalli, PhD, Junwen John Wang, PhD,
Mary E.
Putt, ScD, PhD
Transcriptional
Genomics in Human Heart Failure
Choosing
appropriate
candidate genes is a critical step in pharmacogenomic research, yet our
usual
approaches limit candidates under consideration to our current
understanding of
disease pathogenesis and drug mechanism.
This knowledge is usually incomplete and biased toward findings
from
animal models. We have developed a
complementary approach to selecting candidate genes that focuses on
transcription factors (TFs) and the target genes they regulate
(TF-targets)
using data from human subjects. We call
this approach “transcriptional genomics>”
It involves integration of multiple types of data including
genome
sequence data from -5kb promoter regions, cross-species conservation,
knowledge
of vertebrate transcription factor DNA binding specificity, and human
gene
expression data. The central aim of our
proposal is to refine and apply transcriptional genomics in order to
determine
promising gene variants to test in human heart failure populations. We have assembled and interdisciplinary team
from the Departments of Medicine, Genetics, and Biostatistics to
accomplish
this task. In Aim 1 we will refine
transcriptional genomics methods and apply them to two high quality
gene-expression datasets to select candidate TFs and TF-targets of
direct
relevance to human heart failure. In Aim
2, we will determine genetic variants in candidate TFs and in the
promoter
regions of TF-targets for subsequent pharmacoepidemiologic
investigation in
heart failure populations. This research
will refine a novel interdisciplinary method that identifies
transcriptional
pathways of direct importance to human disease.
The specific candidates we identify in human heart failure will
be the
focus of subsequent R01 applications that propose laboratory- and
population-based pharmacogenomic studies.