Genetic dissection of Cardiac Conduction System homeostasis and Repair
- Institution
- UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON, TX
- Principal investigator
- Jun Wang
- Funding
- $628K
- Duration
- 2018–2027
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Abstract
ABSTRACT The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats. CCS defects commonly give rise to arrhythmia, a leading cause of morbidity and death worldwide. Despite its importance, the molecular mechanisms underlying CCS homeostasis and regeneration are poorly understood. Hippo signaling, a fundamental molecular signaling pathway, inhibits cardiomyocyte proliferation and regeneration. However, the role of Hippo signaling in the CCS is largely unclear. We made the first evidence of an essential role for the Hippo signaling in maintaining CCS homeostasis and repair after injury, which functions via the canonical Hippo signaling mediated by Hippo downstream effectors Yap and Taz. Deletion of Hippo signaling Lats1 and Lats2 in the CCS caused disrupted CCS homeostasis and cardiac arrhythmias in adult mice, which is rescued via genetic deletion of Yap/Taz in the CCS. However, upon CCS injury, Lats1/2 deletion is protective and improved cardiac function. Our preliminary data also suggested a crosstalk between the Hippo and TGF-β signals, as well as Yap/Taz interactions with different transcription factors in no-injury and injury CCS. Here we will further study these findings at the single-cell level to provide unprecedented and novel mechanistic insight(s) into the molecular regulatory mechanisms of the CCS. We are aimed to identify therapeutic targets applicable to the future treatment of human patients with CCS dysfunction and regenerative medicine.
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