Project 1: Ionic Modulation of Chromatin in Cancer

项目 1：癌症中染色质的离子调节

基本信息

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
项目类别：
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

项目摘要

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，通常是最近的研究表明，侵袭性和高度转移性乳房以及。多发性骨髓瘤癌细胞维持的钾浓度比匹配细胞高 200-300% 由于最强的物理化学相互作用涉及可逆染色质。凝结是静电的，原子核离子环境中的任何扰动，例如驱动的扰动通过细胞钾含量的病理生理学升高，预计会对因此，这一发现具有全球性的生理意义。它还有可能统一显示钾水平升高的各种报告。抑制细胞死亡信号通路，以及作用于已知的大量离子通道蛋白在这项提议中，我们检验了细胞内变化的假设。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) 探究肿瘤细胞中染色质结构的物理水平；钾升高与人类肿瘤的临床分期和分级有关；c) 测试癌细胞的这一方面是否存在生理学可用于设计新的联合化疗。在多个长度尺度上进行：从完整的活细胞到分离的细胞核到中期染色体最后是核小体核心颗粒，了解癌症中的离子失衡可能有助于重新利用。目前 FDA 批准的药物，例如通过调节细胞内钾水平起作用的利尿剂，与目前的癌症化疗药物组合的使用将进行测试。通过与 Patient Derived Xenograph Core 合作，治疗包括胶质母细胞瘤在内的多种癌症 Core 的一系列分期和基因分型 GBM 肿瘤系直接与总体相关。 CR-PSOC“癌症中染色质时空动力学和信息传递”的框架通过研究核环境中对癌症很重要的物理化学变化项目 1 研究人员将解决细胞钾浓度变化如何影响进展染色质浓缩及其如何导致恶性表型。跨学科团队将与项目 3 合作确定染色质压缩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的潜在作用该中心项目1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。