Function and Mechanism of the Intercalated Disc Protein XinB in Cardiomyocyte Proliferation and Cardiac Regeneration

闰盘蛋白XinB在心肌细胞增殖和心脏再生中的作用及机制

• 批准号: 10681642
• 负责人: Da-Zhi Wang
• 金额: $ 56.36万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681642
• 关键词: Adaptor Signaling Protein; Adherens Junction; Adult; Affect; Age; Binding; Biochemical; Biological Process; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Cell Nucleus; Cell Proliferation; Cells; Complex; DNA Sequence Alteration; Defect; Development; Disease; Elderly; Feedback; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Giant Cells; Healthcare; Heart; Heart Abnormalities; Heart Diseases; Human; Impairment; Incidence; Intercalated disc; Intercellular Junctions; Knock-out; Knockout Mice; Link; Location; Maintenance; Malignant Neoplasms; Mechanics; Mediating; Molecular; Mutant Strains Mice; Myocardial Contraction; Myocardium; N-Cadherin; Natural regeneration; Neurofibromin 2; Nodal; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Play; Population; Process; Proliferating; Protein Kinase; Proteins; Publishing; Regulation; Regulatory Pathway; Reporting; Repression; Role; Series; Signal Transduction; Structure; Subcellular structure; System; Testing; Therapeutic Intervention; Translations; Work; beta catenin; cardiac regeneration; cardiogenesis; cell growth; cofactor; design; heart function; human disease; new therapeutic target; novel; overexpression; paralogous gene; postnatal; programs; success; targeted treatment; therapy development; tissue repair; transcription regulatory network; transmission process

ABSTRACT Cardiovascular diseases remain the leading cause of death in humans, yet the molecular mechanisms underlying these devastating conditions have not been fully elucidated. Cardiac disease is especially common in the elderly, and as the global population ages their elevated incidence will pose a serious healthcare challenge. An important structure in heart muscle cells is the intercalated disc (ICD), which mediates the coordination of the cardiac syncytium. It functions by connecting neighboring cardiomyocytes, thereby maintaining the functional integrity of this syncytium; this is crucial to the proper contraction of the heart. Although many reports demonstrate the importance of ICDs in the organization of the myocardium, relatively little is known about how these cell-to-cell junctions transmit information between cardiac muscle cells to modulate gene expression and cardiac function. The Xin-repeat containing adaptor proteins Xinα and Xinβ, also called XIRP1 and XIRP2 respectively, were first discovered by the PI. These two proteins are located in the ICD of adult cardiomyocytes and interact with various adherens junction proteins including N-cadherin and β-catenin, supporting an essential role for them in the formation/maintenance of this structure. They also play important roles during early cardiac development and in the pathogenesis of heart disease. However, the role of the Xin proteins remains poorly studied and their specific cellular and molecular functions are largely unknown. Our recent studies of the hearts of Xin knock-out (KO) mice have identified defects in development associated with impaired cardiomyocyte proliferation. Our studies further demonstrated a physical and genetic interaction between Xin and NF2, a component of the important Hippo/YAP pathway. The Hippo-YAP pathway is a highly conserved cellular regulatory network that has been previously implicated in multiple developmental systems and disease, including the heart; however, the mechanisms of its action remain unclear and a link to the ICD is a novel and exciting new discovery. Therefore, we have designed two integrative Specific Aims to test the mechanism by which the ICD protein Xin mediates cardiomyocyte proliferation, maturation, and regeneration. For the first Aim, we will investigate the interaction between Xin and the Hippo/YAP pathway. We will study how Xin regulates YAP activity and how the interaction between Xin and Hippo-YAP signaling regulates cardiac function and regeneration. For the second Aim, we will study how YAP/Tead1 regulates Xin transcription and test our hypothesis that Xin-YAP cross-regulation is crucial to cardiac gene expression and heart regeneration. The studies proposed here will reveal novel molecular mechanisms by which the important pathophysiological Hippo/YAP signal is modulated by the ICD protein Xin in the heart. The molecules defined in this study will become targets for therapeutic intervention in the treatment of cardiac diseases.

抽象的 心血管疾病仍然是人类死亡的主要原因，但其分子机制 这些破坏性条件的根本原因尚未完全阐明。心脏病尤其常见 在老年人中，随着全球人口老龄化，其发病率升高将构成严重的医疗保健挑战。 心肌细胞的一个重要结构是闰盘（ICD），它介导心肌细胞的协调 心脏合胞体。它通过连接邻近的心肌细胞发挥作用，从而维持功能 该合胞体的完整性；这对于心脏的正常收缩至关重要。虽然很多报道 证明了 ICD 在心肌组织中的重要性，但人们对它如何发挥作用知之甚少 这些细胞与细胞的连接在心肌细胞之间传递信息以调节基因表达和 心脏功能。 含有接头蛋白 Xinα 和 Xinβ 的 Xin 重复序列，也分别称为 XIRP1 和 XIRP2， 最先由 PI 发现。这两种蛋白位于成体心肌细胞的 ICD 中，并与 各种粘附连接蛋白，包括 N-钙粘蛋白和 β-连环蛋白，支持它们在 该结构的形成/维护。它们在早期心脏发育过程中也发挥着重要作用 以及心脏病的发病机制。然而，Xin 蛋白的作用仍然缺乏研究，而且它们的作用 特定的细胞和分子功能很大程度上是未知的。我们最近对 Xin 敲除心脏的研究 (KO) 小鼠已发现与心肌细胞增殖受损相关的发育缺陷。我们的 研究进一步证明了 Xin 和 NF2 之间的物理和遗传相互作用，NF2 是 重要的 Hippo/YAP 途径。 Hippo-YAP 通路是一个高度保守的细胞调节网络， 以前曾与多种发育系统和疾病有关，包括心脏；然而， 其作用机制尚不清楚，与 ICD 的联系是一个新颖且令人兴奋的新发现。 因此，我们设计了两个综合的具体目标来测试 ICD 的机制。 Xin 蛋白介导心肌细胞增殖、成熟和再生。为了第一个目标，我们 将研究 Xin 与 Hippo/YAP 通路之间的相互作用。我们将研究Xin如何监管YAP 活性以及 Xin 和 Hippo-YAP 信号之间的相互作用如何调节心脏功能和 再生。对于第二个目标，我们将研究 YAP/Tead1 如何调节 Xin 转录并测试我们的 假设 Xin-YAP 交叉调节对心脏基因表达和心脏再生至关重要。 这里提出的研究将揭示重要的新分子机制 病理生理学 Hippo/YAP 信号由心脏中的 ICD 蛋白 Xin 调节。分子定义 这项研究将成为治疗心脏病的治疗干预的目标。