Regulation of TRPM7 Channels

TRPM7 通道的调节

• 批准号: 9974402
• 负责人: LOREN W RUNNELS
• 金额: $ 1.16万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9974402
• 关键词: Binding; Biochemical; Cardiac; Cardiac development; Cells; Clinical; Complex; Data; Disease; Electrophysiology (science); Family; Fibroblasts; Goals; Half-Life; Heart Diseases; Heart Hypertrophy; Heart failure; Image; Individual; Instruction; Investigation; Ion Channel; Lead; Link; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Molecular; Nature; Neoplasm Metastasis; PTP4A2 gene; Pathologic; Pathology; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Play; Process; Protein Kinase; Proteins; Proteomics; Regulation; Reporting; Research; Role; Site; Stroke; Testing; Therapeutic Intervention; cancer cell; cancer therapy; coronary fibrosis; fibrogenesis; imaging approach; in vivo; member; mouse model; neuron loss; novel; protein expression; response; stroke therapy; targeted treatment

PROJECT SUMMARY Excessive TRPM7 channel activity is linked to neuronal cell death, cancer cell metastasis, and as our preliminary data will demonstrate, the development of cardiac fibrosis in a hypertensive hypertrophy/heart failure mouse model. Collectively, these findings underscore a critical role for TRPM7 in the pathology of a multitude of diseases, making channel an attractive target for therapeutic intervention. However, the specific mechanisms controlling TRPM7 activity in vivo remain unknown. We have made the critical discovery that TRPM7 binds to CNNM proteins (CNNM1-4), which our preliminary data indicate function as regulatory subunits of the channel. We further show that PTP4A phosphatases activate TRPM7 in a CNNM-dependent manner. TRPM7 is the first identified ion channel to possess a kinase domain, the function of which is poorly understood. We recently reported the discovery that auto-phosphorylation of the channel plays a decisive role in controlling the stability of TRPM7 protein expression and the channel's localization in cells. We hypothesize that PTP4A phosphatases, CNNMs, and channel phosphorylation operate in concert to regulate TRPM7. In the multi-PI proposal, we propose three specific aims to elucidate the molecular mechanisms controlling the TRPM7 channel with the long-term goal of understanding how the channel becomes upregulated during cardiac fibrosis. In specific aim 1, we will employ electrophysiology, imaging, and biochemical approaches to elucidate the regulation of TRPM7 by CNNMs and PTP4As. In specific aim 2, we will apply analytical mass spectrometry, biochemical, and imaging approaches to understand how phosphorylation of the channel regulates TRPM7 protein expression and its cellular localization. In specific aim 3, we will investigate the specific mechanism(s) controlling pathological stimulation of the channel during cardiac fibrosis. There is an urgent need for new treatments for stroke, cancer, and heart disease, which kill or severely disable millions of individuals each year. Results from our investigation will have a significant impact by uncovering the mechanisms controlling the channel, which may lead to novel clinical approaches for blocking TRPM7's pathological actions in these devastating diseases.

项目概要 过度的 TRPM7 通道活性与神经元细胞死亡、癌细胞转移有关，并且我们的研究 初步数据将证明，高血压肥厚/心脏中心脏纤维化的发展 失败的小鼠模型。总的来说，这些发现强调了 TRPM7 在 a 病理学中的关键作用 多种疾病，使通道成为治疗干预的有吸引力的目标。不过，具体 体内控制 TRPM7 活性的机制仍不清楚。我们已经做出了重要的发现 TRPM7 与 CNNM 蛋白 (CNNM1-4) 结合，我们的初步数据表明其具有调节功能 通道的子单元。我们进一步表明，PTP4A 磷酸酶在 CNNM 依赖性中激活 TRPM7 方式。 TRPM7是第一个被鉴定的具有激酶结构域的离子通道，其功能很差 明白了。我们最近报道了通道的自身磷酸化起着决定性作用的发现 控制 TRPM7 蛋白表达的稳定性和通道在细胞中的定位。我们假设 PTP4A 磷酸酶、CNNM 和通道磷酸化协同作用来调节 TRPM7。在 多PI提案中，我们提出了三个具体目标来阐明控制 TRPM7 通道的长期目标是了解该通道在 心脏纤维化。在具体目标 1 中，我们将采用电生理学、成像和生化方法来 阐明 CNNM 和 PTP4As 对 TRPM7 的调节。在具体目标 2 中，我们将应用分析质量 光谱、生化和成像方法来了解通道的磷酸化 调节 TRPM7 蛋白表达及其细胞定位。在具体目标 3 中，我们将调查 控制心脏纤维化过程中通道病理刺激的特定机制。有一个 中风、癌症和心脏病迫切需要新的治疗方法，这些疾病导致数百万人死亡或严重残疾 每年都有个人。我们的调查结果将通过揭露问题产生重大影响 控制通道的机制，这可能会导致阻断 TRPM7 的新临床方法 这些毁灭性疾病的病理作用。