Project Details
Description
TITIN (TTN) truncating variants (TTNtvs) have been found to be the most common genetic factor for
dilated cardiomyopathy (DCM). However, allelic heterogeneity (AH) of TTNtv DCM, i.e. TTNtvs are also
found in reference populations, significantly confound diagnosis and therapeutic development of these
patients. Pathogenic TTNtvs are mainly found in the C-terminal A-band region (TTNtv-As) but less in the
N-terminal Zdisc region (TTNtv-Zs). Moreover, pathological signaling pathways for TTNtv DCM remain
largely unknown. Here, we aim to leverage unique research opportunities enabled by zebrafish genetics
to decipher underlying mechanisms of AH, discover pathological signaling pathways, and develop
effective therapeutic avenues. Our preliminary studies showed that AH of TTNtv DCM can be
recapitulated in both embryonic and adult zebrafish, opening the door for mechanistic studies of AH in
vivo. From our screen of known cardiomyopathy signaling pathways, we identified mTOR, autophagy,
MAPK and PDE1 as candidate signaling pathways that could be leveraged for therapeutic benefits. We
also established a F0-based genetic assay using the Microhomologymediated end joining (MMEJ)
genome editing technology that enables us to rapidly discover new signaling pathways. Based on these
preliminary studies, we proposed to leverage unique genetic and chemical genetic tools in zebrafish to
prove that zebrafish is the first in vivo animal model for allelic heterogeneity of TTNtv DCM, which can
be used to decipher primary damages incurred by TTNtvs, to discover sequential pathological signaling
pathways, and to develop mechanism-based therapies. The proposal is organized into the 3 specific
aims. In Specific Aim 1, we will decipher allelic heterogeneity of ttntv DCM via studying a panel of ttntv
mutants and ttn null mutants. In Specific Aim 2, we propose to elucidate molecular basis of autophagy
dysregulation in ttntv DCM and develop an autophagy-based therapy. In Specific Aim 3, we will confirm
MAPK and PDE1 as candidate signalings and discover additional new genes and signaling pathways by
carrying MMEJ-based F0 screens. Upon completion of the proposal, we anticipate the following
deliverables: 1) provide in vivo evidence to clarify why TTNtv-As are more likely to cause DCM
phenotypes than TTNtv-Zs; 2) obtain insights on autophagy, MAPK and PDE signaling pathways in ttntv
DCM, and identify mechanism-based therapeutic avenues for ttntv DCM; 3) establish a F0-based genetic
screening approach that is capable of systematically discovering new genes for ttntv DCM, opening an
unprecedented opportunity for mechanistic studies of an inherited cardiomyopathy
Status | Active |
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Effective start/end date | 8/1/05 → 6/30/24 |
Funding
- National Heart, Lung, and Blood Institute: $348,551.00
- National Heart, Lung, and Blood Institute: $348,551.00
- National Heart, Lung, and Blood Institute: $358,961.00
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