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.

项目摘要 房室特有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没有被探索过。在初步研究中，我们分析了 比较LV和RV在新生小鼠心脏中的关键细胞内信号活性，发现 P38MAPK在RV中表现出独特的小室特异性和发育阶段特异性模式 在新生儿到青春期的过渡期间。值得注意的是，心肌细胞特异性的p38活性失活在 小鼠心脏发育导致致死性心肌病与RV特异性诱导心肌细胞相关 新生小鼠心脏的增殖和肥厚，而对左心室的影响最小。此外，IRE1α- XBP1轴在p38介导的心肌细胞增殖调控中是必不可少的下游信号。已被占用 综上所述，这些发现首次揭示了先前确定的两种与应激有关的致病因素 信号通路p38MAPK和IRE1α/XBP1在正常的小室特异性表达中也起着不可或缺的作用。 胎儿向成人过渡过程中出生后心脏的发育。在这份提案中，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 IRE1α/XBP1轴在靶向新的小鼠心脏发育模型中的作用 IRE1α/XBP1活性的调控。2)p38介导的IRE1α/XBP1轴的特异性贡献 出生后心脏发育过程中室壁特异性生长的调节。3)发现下游目标 出生后心脏p38/IRE1、α/XBP1信号的室特异性调控。这些研究将 首次建立了细胞内信号网络，用于特定房间的出生后发育 新生儿心脏，填补了我们目前在心脏生物学这一重要领域的知识的一个关键空白。