Novel Signaling Mechanism in Chamber-Specific Postnatal Heart Growth

腔室特异性产后心脏生长的新型信号机制

• 批准号: 10583889
• 负责人: Tomohiro Yokota
• 金额: $ 39万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583889
• 关键词: Adolescent; Adult; Affect; Apoptosis; Area; Biology; Birth; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cells; Cellular Stress; Data; Development; Fetal Development; Fetal Heart; Foundations; Functional disorder; Future; Genetic Transcription; Genomics; Growth; Heart; Heart Diseases; Hypertrophy; In Vitro; Inflammatory; Injury; Knowledge; Left; Light; MAP Kinase Gene; Mammals; Measures; Mediating; Mitogen-Activated Protein Kinases; Molecular; Mus; Muscle Cells; Neonatal; Newborn Infant; Outcome; Outcome Study; Pathogenicity; Pathway interactions; Pattern; Perinatal; Peripheral; Physiological; Physiology; Process; Proliferating; Proteome; Pulmonary Circulation; Regenerative Medicine; Regulation; Reporting; Research Personnel; Role; Signal Transduction; Specificity; Stress; Stress Response Signaling; Time; Tissues; Transgenic Mice; Weight; XBP1 gene; cardiogenesis; cardioprotection; cell type; congenital heart disorder; endoplasmic reticulum stress; fetal; heart dimension/size; heart function; hemodynamics; in vivo Model; interdisciplinary approach; mouse model; neonatal mice; novel; p38 MAPK Signaling Pathway; p38 Mitogen Activated Protein Kinase; pharmacologic; postnatal; postnatal development; stem cell biology; tool

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.

项目概要 腔室特定的出生后生长是出生后心脏发育的基石，然而， 潜在的分子机制几乎完全未被探索。在初步研究中，我们分析并 比较了新生小鼠心脏中 LV 和 RV 之间的关键细胞内信号传导活动，发现 p38 MAP 激酶激活在 RV 中表现出独特的室特异性和发育阶段特异性模式 在新生儿到青少年的过渡期间。引人注目的是，心肌细胞中 p38 活性的特异性失活 发育中的小鼠心脏导致与 RV 特异性诱导心肌细胞相关的致死性心肌病 新生小鼠心脏增殖和肥大，而左心室受到的影响最小。此外，IRE1α- Xbp1 轴是 p38 介导的心肌细胞增殖调节中必不可少的下游信号传导。采取 总之，这些发现首次揭示了两种先前确定的与应激相关的致病性 信号通路 p38 MAPK 和 IRE1α/Xbp1 也是正常腔室特异性中不可或缺的参与者 胎儿到成人过渡期间产后心脏的发育。在这个提案中，我们的目标是探索这部小说 通过实现以下三个具体目标来发现。目标 1)：确定功能和分子影响 使用具有靶向作用的新型小鼠模型研究 IRE1α/Xbp1 轴在腔室特异性产后心脏发育中的作用 IRE1α/Xbp1 活性的操纵。 2) 建立IRE1α/Xbp1轴在p38介导中的特异性贡献 出生后心脏发育过程中腔室特异性生长的调节。 3）发现下游目标 出生后心脏中 p38/IRE1α/Xbp1 信号传导的潜在腔室特异性调节。这些研究将 首次建立了用于腔室特异性产后发育的细胞内信号网络 新生儿心脏并填补了我们当前在心脏生物学这一重要领域的知识的关键空白。