LncRNA mechanism of heart failure

  • Chang, Ching-Pin, (PI)

Project: Research project

Project Details

Description

Project Summary/Abstract
Pathological stress induces transcriptional gene reprogramming in the heart muscle, leading to
cardiac myopathy and heart failure. Such stress-induced gene reprogramming requires regulation at
the chromatin level by chromatin-regulating factors. The activity of chromatin regulators can be
modulated by an emerging class of RNAs-the long noncoding RNAs (lncRNAs), which are
long RNA
transcripts with low/no protein-coding potential. The role of lncRNAs in hypertrophy and heart failure,
however, is essentially unknown. Most studies of lncRNAs are conducted in cell cultures or in yeast,
and mouse genetic models are lacking. This program will focus on a new mouse genetic model to
define the molecular function of a newly identified lncRNA in controlling cardiac gene expression,
hypertrophy, and failure. Because RNAs can be chemically modified and delivered as a drug for
therapy, the success of this program will lay down a foundation for designing new mechanism-based
therapy for heart failure.
Aim 1: Defining the in vivo regulation of an lncRNA in the heart. We will use transgenic and knockout
technology of mouse genetics to define the genetic and molecular mechanisms by which this lncRNA
expression is regulated in the heart. Methods also include immunostaining, western blot, quantitative
PCR, chromatin immunoprecipitation (ChIP), and RNA immunoprecipitation (RNA-IP) analyses.
Aim 2: Determining how this lncRNA interacts with chromatin-regulating factor in the heart. We will
use molecular, cellular, and biochemical methods to determine the molecular mechanism by which
the lncRNA controls the molecular functions of chromatin regulators in the hearts. The methods
include RNA-IP, ChIP, quantitative PCR, electric mobility shift assays, episome-based reporter
assays, and nucleosome assembly.
Aim 3: Defining the function of human lncRNA-protein complex. We will use human heart tissues and
iPS-derived heart cells to demonstrate the presence of lncRNA complex. Also, we will use molecular,
cellular, and biochemical methods to define the function of human lncRNA complex. The methods
include RNA-IP, ChIP analysis of small amount of tissues, quantitative PCR, electric mobility shift
assays, episome-based reporter assays, and iPS-based technology.
StatusFinished
Effective start/end date4/1/143/31/18

Funding

  • National Institutes of Health: $400,438.00
  • National Institutes of Health: $401,539.00
  • National Institutes of Health: $394,948.00

ASJC

  • Medicine(all)

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