Interaction of ASIC and BK channels and its role in glial proliferation

ASIC 和 BK 通道的相互作用及其在胶质细胞增殖中的作用

• 批准号: 8100816
• 负责人: Elena Petroff
• 金额: $ 32.07万
• 依托单位: MONTCLAIR STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2016-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100816
• 关键词: ASIC channel; Acidosis; Address; Affect; Area; Brain; Brain Injuries; Brain Neoplasms; Calcium; Cell Proliferation; Data; Data Analyses; Defense Mechanisms; Disease; Drops; Environment; Future; Glial Cell Proliferation; Glioblastoma; Glioma; Growth; Injury; Investigation; Ion Channel; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Molecular; Mutagenesis; Nervous System Trauma; Neuroglia; Patients; Potassium Channel; Principal Investigator; Process; Proliferating; Publications; Regulation; Research; Research Project Grants; Research Training; Role; Science; Site; Stroke; Students; Testing; Tissues; Toxin; Trauma; Wild Type Mouse; Work; base; career; cell growth; channel blockers; design; experience; extracellular; fighting; graduate student; inhibitor/antagonist; insight; large-conductance calcium-activated potassium channels; migration; mutant; novel; novel strategies; outcome forecast; patch clamp; rapid growth; research study; response; symposium; synthetic peptide; tumor growth; tumor progression; voltage

DESCRIPTION (provided by applicant): Glial tumors carry very poor prognosis due to their rapid growth and invasive migration. The mechanism(s) that trigger glial growth, especially those leading to increased proliferation, could be important for treatment; however, they remain largely unknown. The survival of patients with glioblastoma multiforme, for example, is on average 12 months, despite most aggressive treatments, and this prognosis has remained unchanged for the past 30 years. Therefore, new approaches are required to address this problem. This project proposes to test a novel hypothesis that involves the interaction of two ion channels: the large conductance calcium- and voltage-activated potassium channels (BK) and acid-sensing ion channels (ASICs). BKs are expressed in normal glial cells and in gliomas and have been shown to potentiate cell proliferation; their blockers inhibit glioma cell growth. Functional regulation of BK channel activity could contribute to glial proliferation. Both normal glia and glioma tissues express ASICs that inhibit BKs in a pH-dependent manner, and the expression of ASICs changes with the progression of the tumor. ASICs therefore could act as endogenous inhibitors of BK and related glial growth, until a drop in the extracellular pH (during brain injury, trauma, stroke) leads to the relief of this inhibition. Then, a more active BK promotes glial growth and proliferation. To test the hypothesis that dysregulation of ASIC-BK interaction leads to increased proliferation of glia, the following specific aims are proposed: 1) to determine the molecular mechanisms involved in ASIC1a-BK interaction in glial cells; 2) to determine the effects of ASIC1a-BK interaction on cell growth, proliferation, and migration. This proposal represents a unique opportunity for an undergraduate and a master's student to perform experiments in the area of glial and tumor growth in a real research lab setting. The students, under the guidance of the principal investigator, will perform this small-scale research project that will yield important data. The project will provide laboratory training and research experience, and prepare the students for future graduate work and careers in biomedical science. The estimated duration of this project is three years. PUBLIC HEALTH RELEVANCE: Glial tumors carry very poor prognosis due to their rapid growth. The survival of patients with glioblastoma multiforme, for example, is an average of 12 months, and this prognosis has remained unchanged for the past 30 years. New approaches are required to address this problem. This project proposes to test a novel hypothesis that acidosis-dependent regulation of the large conductance calcium- and voltage-activated potassium channels that promote glial growth, by their endogenous blockers, acid-sensing ion channels, could contribute to glial proliferation. This proposal represents a unique opportunity for an undergraduate and a master's student to perform experiments in the area of glial growth and potential tumorogenesis, to contribute to scientific knowledge and to our efforts to fight this devastating disease.

描述（由申请人提供）：胶质肿瘤由于其快速生长和侵入性迁移而具有很差的预后。引发神经胶质增长的机制，尤其是导致增殖增加的机制，对于治疗可能很重要。但是，它们在很大程度上仍然未知。例如，胶质母细胞瘤患者的生存率平均为12个月，尽管疗法大多，但在过去的30年中，这种预后一直保持不变。因此，需要新的方法来解决此问题。该项目提出了一个新的假设，涉及两个离子通道的相互作用：大电导钙和电压激活的钾通道（BK）和酸 - 敏感性离子通道（ASICS）。 BK在正常的神经胶质细胞和神经胶质瘤中表达，并已显示可增强细胞增殖。他们的阻滞剂抑制神经胶质瘤细胞的生长。 BK通道活性的功能调节可能有助于神经胶质增殖。正常胶质瘤和神经胶质瘤组织都表达了以pH值依赖性抑制BK的ASIC，并且ASIC的表达随肿瘤的进展而变化。因此，ASIC可以充当BK和相关神经胶质生长的内源性抑制剂，直到细胞外pH值下降（在脑损伤期间，创伤，中风）导致这种抑制作用。然后，更活跃的BK促进了神经胶质的生长和增殖。为了测试ASIC-BK相互作用失调导致神经胶质增殖的增加的假设，提出了以下特定目的：1）确定胶质细胞中ASIC1A-BK相互作用的分子机制； 2）确定ASIC1A-BK相互作用对细胞生长，增殖和迁移的影响。该提案代表了本科生和硕士学生在真正的研究实验室中进行神经胶质和肿瘤生长领域进行实验的独特机会。在首席研究人员的指导下，学生将执行这个小规模的研究项目，该项目将产生重要的数据。该项目将提供实验室培训和研究经验，并为学生做好准备的未来研究生工作和生物医学科学职业的准备。该项目的估计持续时间为三年。 公共卫生相关性：胶质肿瘤由于快速生长而具有非常差的预后。例如，多形胶质母细胞瘤患者的存活率平均为12个月，在过去的30年中，这种预后一直保持不变。需要新的方法来解决此问题。该项目提出了一个新的假设，即酸中毒依赖性调节大型电导钙和电压激活的钾通道，该通道通过其内源性阻滞剂，酸性离子通道促进神经胶质生长，可能有助于神经胶质增殖。该提议为本科生和硕士学生提供了在神经胶质生长和潜在肿瘤发生领域进行实验的独特机会，为科学知识做出了贡献，以及我们努力抵抗这种毁灭性疾病的努力。