# Novel Signaling Mechanism in Chamber-Specific Postnatal Heart Growth

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $390,000

## Abstract

Project Summary
 Chamber specific postnatal growth is the cornerstone of postnatal heart development, however, the
underlying molecular mechanisms are almost entirely unexplored. In preliminary studies, we analyzed and
compared key intracellular signaling activities between LV and RV in neonatal mouse hearts and discovered that
p38 MAP kinase activation displayed a unique chamber-specific and developmental stage specific pattern in RV
during neonatal to adolescent transition. Strikingly, cardiomyocyte specific inactivation of p38 activity in the
developing mouse heart led to lethal cardiomyopathy associated with RV specific induction of myocyte
proliferation and hypertrophy in neonatal mouse heart while the LV was minimally affected. Furthermore, IRE1α-
Xbp1 axis is essential downstream signaling in p38 mediated regulation of cardiomyocyte proliferation. Taken
together, these findings reveal for the first time that two previously established pathogenic stress-related
signaling pathways, p38 MAPK and IRE1α/Xbp1, are also indispensable players in normal chamber specific
development in postnatal heart during fetal to adult transition. In this proposal, we aim to explore this novel
finding by accomplishing the following three specific aims. Aim 1): Determine the functional and molecular impact
of IRE1α/Xbp1 axis in chamber-specific postnatal heart development using novel mouse models with targeted
manipulation of IRE1α/Xbp1 activity. 2) Establish the specific contribution IRE1α/Xbp1 axis in p38 mediate
regulation of chamber-specific growth during postnatal heart development. 3) Uncover downstream targets
underlying chamber specific regulation of p38/IRE1α/Xbp1 signaling in postnatal heart. These studies will
establish for the first time an intracellular signaling network for chamber-specific postnatal development in
neonatal heart and fill a critical gap in our current knowledge in this important area of cardiac biology.

## Key facts

- **NIH application ID:** 10583889
- **Project number:** 1R01HL163025-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Tomohiro Yokota
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $390,000
- **Award type:** 1
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10583889

## Citation

> US National Institutes of Health, RePORTER application 10583889, Novel Signaling Mechanism in Chamber-Specific Postnatal Heart Growth (1R01HL163025-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10583889. Licensed CC0.

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