Project 1: Ionic Modulation of Chromatin in Cancer

项目 1：癌症中染色质的离子调节

• 批准号: 8866970
• 负责人: THOMAS V O'HALLORAN
• 金额: $ 41.42万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-19 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8866970
• 关键词: Accounting; Address; Animal Model; Apoptosis; Architecture; Breast; Cell Death; Cell Death Signaling Process; Cell Line; Cell Nucleus; Cell physiology; Cells; Characteristics; Chromatin; Chromatin Structure; Chromosome Structures; Chromosomes; Clinical; Clinical Trials; Collaborations; Combination Drug Therapy; Disease Progression; Diuretics; Drug Combinations; Electrostatics; Environment; FDA approved; Gene Expression; Gene Expression Profile; Genotype; Glioblastoma; Goals; Higher Order Chromatin Structure; Human; Ion Channel Protein; Ionic Strengths; Ions; Lead; Length; Life; Malignant Neoplasms; Maps; Measurement; Metabolism; Metaphase; Methods; Molecular; Multiple Myeloma; Nuclear; Nucleosome Core Particle; Nucleosomes; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Physical Chemistry; Physical condensation; Physiological; Physiological Processes; Play; Potassium; Potassium Channel; Reporting; Research Personnel; Role; Series; Signal Pathway; Spectrum Analysis; Staging; Testing; Therapeutic Agents; Therapeutic Intervention; Work; Xenograft procedure; cancer cell; cancer therapy; chemotherapy; density; design; insight; leukemia; malignant breast neoplasm; malignant phenotype; member; neoplastic cell; novel therapeutics; research study; theories; tumor; tumor progression; tumorigenic

ABSTRACT (PROJECT 1) Intracellular potassium levels play a central role in regulating physiological processes and are generally maintained within narrow limits. Recent studies reveal that aggressive and highly metastatic breast as well as multiple myeloma cancer cells maintain potassium concentrations that are 200-300% higher than matched non-tumorigenic cells. Since the strongest physicochemical interactions involved in reversible chromatin condensation are electrostatic, any perturbations in the ionic environment of the nucleus, such as those driven by a pathophysiological elevation of cellular potassium content, are anticipated to have profound effects on chromatin structure and access to transcriptional machinery. Thus this discovery has global physiological implications. It also has the potential to unify a variety of reports showing that elevated potassium levels suppress cell death signaling pathways, as well as acting on the large number of ion channel proteins known to play a role in cancer progression. In this proposal we test the hypothesis that alterations in intracellular potassium levels alter chromatin structure and nuclear organization and consequently, global gene expression. To address this hypothesis we will develop new physical methods to: a) understand the impact of potassium concentration on chromatin structure at the physical level in tumor cells; b) probe the relationship between elevated potassium and clinical stage and grade of human tumors; and c) test whether this facet of cancer cell physiology can be exploited for the design of new combination chemotherapies. These experiments will be performed across multiple length scales: from intact living cells to isolated nuclei to metaphase chromosomes and finally on nucleosome core particles. Understanding ion imbalances in cancer may allow the repurposing of current FDA-approved agents, such as diuretics that work by modulating intracellular potassium levels, for use in combination with current chemotherapies for cancer treatment. Drug combinations will be tested in several cancers, including glioblastoma, through collaboration with the Patient Derived Xenograph Core using the Core's series of staged and genotyped GBM tumor lines. This project connects directly to the overarching framework of the CR-PSOC “Spatio-Temporal Dynamics of Chromatin and Information Transfer in Cancer” through the study of physiochemical changes in the nuclear environment that are important in cancer progression. Project 1 investigators will address how changes in cellular concentration of potassium impact chromatin condensation and how this contributes to the malignant phenotype. Members of this transdisciplinary team will work in collaboration with Project 3 to determine the extent of chromatin compaction in intact nuclei, and with members of Project 2 to examine the potential roles for potassium accumulation in leukemia. The role of Project 1 in the Center is to resolve key electrostatic features of the cancer cell nucleus and then apply the new insights to understand, and ultimately intervene in disease progression.

摘要（项目1） 细胞内钾水平在调节生理过程中起着核心作用，并且通常是 保持在狭窄的范围内。最近的研究表明，侵袭性和高转移性乳腺癌以及 多发性骨髓瘤癌细胞保持钾浓度比匹配的高200- 300 非致瘤细胞。由于可逆染色质中最强的物理化学相互作用 凝聚是静电的，在原子核的离子环境中的任何扰动，例如那些被驱动的 通过细胞钾含量的病理生理升高，预计对 染色质结构和进入转录机器。因此，这一发现具有全球性的生理学意义。 含义。它也有可能统一各种报告，表明钾水平升高 抑制细胞死亡信号通路，以及作用于大量的离子通道蛋白， 在癌症发展中起作用。在这个建议中，我们测试的假设，细胞内的变化， 钾水平改变染色质结构和核组织，从而改变整体基因表达。 为了解决这个假设，我们将开发新的物理方法来：a）了解钾的影响 B）在肿瘤细胞的物理水平上探测浓度对染色质结构的影响; 升高的钾与人类肿瘤的临床分期和分级;以及c）测试癌细胞的这一方面是否 生理学可用于设计新的组合化疗。这些实验将 在多个长度尺度上进行：从完整的活细胞到分离的细胞核再到中期染色体 最后是核小体核心颗粒。了解癌症中的离子不平衡可能会允许重新利用 目前FDA批准的药物，如通过调节细胞内钾水平起作用的利尿剂， 与目前的化学疗法联合用于癌症治疗。药物组合将在 包括胶质母细胞瘤在内的几种癌症，通过与Patient Derived Xenograph Core合作， Core的一系列分期和基因分型的GBM肿瘤系。这个项目直接连接到 CR-PSOC“染色质时空动力学和癌症信息传递”框架 通过研究在癌症中重要的核环境中的物理化学变化， 进展项目1研究人员将研究细胞钾浓度的变化如何影响 染色质凝聚以及这如何导致恶性表型。议员 跨学科团队将与项目3合作，以确定染色质致密化的程度 在完整的细胞核中，并与项目2的成员一起研究钾积累在细胞核中的潜在作用。 白血病项目1在中心的作用是解决癌细胞核的关键静电特征 然后应用新的见解来理解，并最终干预疾病的进展。