Regulation of TRPM7 Channels

TRPM7 通道的调节

• 批准号: 9902531
• 负责人: LOREN W RUNNELS
• 金额: $ 60.91万
• 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/9902531
• 关键词: Binding; Biochemical; Cardiac; Cardiac development; Cells; Clinical; Complex; Data; Disease; Electrophysiology (science); Family; Fibroblasts; Goals; Growth Factor; Half-Life; Heart Diseases; Heart Hypertrophy; Heart Injuries; Heart failure; Image; Individual; Instruction; Investigation; Ion Channel; Lead; Link; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Molecular; Myofibroblast; 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; cytokine; decision research; fibrogenesis; imaging approach; in vivo; member; mouse model; neuron loss; novel; protein expression; response; stroke therapy; targeted treatment

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.

过度的TRPM 7通道活性与神经元细胞死亡、癌细胞转移有关，并且如我们的初步数据将证明的，与高血压肥大/心力衰竭小鼠模型中心脏纤维化的发展有关。总的来说，这些发现强调了TRPM 7在多种疾病的病理学中的关键作用，使通道成为治疗干预的有吸引力的靶点。然而，在体内控制TRPM 7活性的具体机制仍然未知。我们已经发现TRPM 7与CNNM蛋白（CNNM 1 -4）结合，我们的初步数据表明其作为通道的调节亚基起作用。我们进一步表明，PTP 4A磷酸酶以CNNM依赖的方式激活TRPM 7。TRPM 7是第一个被鉴定的具有激酶结构域的离子通道，其功能知之甚少。我们最近报道发现，该通道的自磷酸化在控制TRPM 7蛋白表达的稳定性和该通道在细胞中的定位中起决定性作用。我们假设PTP 4A磷酸酶、CNNM和通道磷酸化协同作用调节TRPM 7。在多PI提案中，我们提出了三个具体目标来阐明控制TRPM 7通道的分子机制，其长期目标是了解该通道在心脏纤维化期间如何上调。在具体目标1中，我们将采用电生理学、成像和生物化学方法来阐明CNNM和PTP 4A对TRPM 7的调节。在具体目标2中，我们将应用分析质谱，生物化学和成像方法来了解通道的磷酸化如何调节TRPM 7蛋白表达及其细胞定位。在具体目标3中，我们将研究在心脏纤维化期间控制通道的病理刺激的具体机制。对于中风、癌症和心脏病的新疗法存在迫切需求，这些疾病每年导致数百万人死亡或严重残疾。我们的研究结果将通过揭示控制该通道的机制产生重大影响，这可能导致新的临床方法来阻断TRPM 7在这些毁灭性疾病中的病理作用。