Structure and Pharmacologic Modulation of the Mitotic Chromosome's Central Axis

有丝分裂染色体中轴的结构和药理学调节

• 批准号: 10704101
• 负责人: Andrew J. Beel
• 金额: $ 39.37万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704101
• 关键词: 3-Dimensional; Acceleration; Affinity; Architecture; Biology; Cellular biology; Chemicals; Chromatin; Chromatin Loop; Chromosomal Instability; Chromosome Condensation; Chromosomes; Clinical; Communities; Cryo-electron tomography; Cryoelectron Microscopy; Development; Disease; Electron Microscope; Ensure; Environment; Equipment; Eukaryota; Event; Evolution; Faculty; Filament; Foundations; Funding; Genetic Transcription; Genome; Genomic Instability; Genomics; Goals; Health; Hematologic Neoplasms; Human; Hydrogels; Institution; Interphase; Investigation; Kinetochores; Knowledge acquisition; Laboratories; Literature; Malignant Neoplasms; Mass Spectrum Analysis; Mentors; Mentorship; Metaphase; Methods; Mitotic; Mitotic Chromosome; Molecular; Nature; Neoplastic Processes; Pathway interactions; Phase Transition; Physical condensation; Play; Positioning Attribute; Procedures; Protocols documentation; RNA Polymerase II; Research; Research Personnel; Resolution; Role; Scientist; Shapes; Site; Societies; Solid; Source; Structure; Therapeutic; Training; Uncertainty; United States National Academy of Sciences; Work; cancer cell; condensin; equipment acquisition; experience; foot; genetic information; high risk; immune clearance; inhibitor; invention; member; next generation sequencing; novel; organizational structure; pharmacologic; professor; scaffold; sequencing platform; small molecule; small molecule inhibitor; structural biology; success; targeted cancer therapy; tenure track; theories; therapy resistant; tool

Project Summary Mitotic chromosome formation is essential for the dissemination of genetic information in eukaryotes. The conversion of dispersed interphase chromatin into the iconic, X-shaped metaphase chromosome involves three principal events: the formation of a central axis (the chromosomal “scaffold”), lengthwise contraction, and condensation. Plausible theories have been advanced to explain the latter two events, with contraction occurring through the extrusion of chromatin loops and condensation occurring through a volume phase transition of the chromosomal material. In contrast, little is known about the formation of the mitotic scaffold, and its very existence has been the source of considerable controversy. Direct evidence for the scaffold's existence has recently come from the observation of a central filament in native mitotic chromosomes subjected to controlled expansion ex vivo. This filament could be liberated, intact, from its chromosomal confines by careful nucleolysis, providing a basis for further study. This proposal aims to elucidate basic principles of the mitotic chromosome scaffold, including its molecular composition (Aim 1), its three-dimensional architecture (Aim 2), and its interactions with the chromatin enveloping it (Aims 1 and 2). The information obtained will provide a global view of the core of the mitotic chromosome, explaining how its components assemble into a structure of mesoscopic proportions and how this structure organizes the genome in a manner ensuring its faithful and efficient distribution. The acquired knowledge will enable more detailed investigations into the mechanisms governing scaffold assembly and disassembly and the nature of its interactions with other cellular components (e.g., chromatin, kinetochores). This proposal also seeks to develop chemical modulators of scaffold assembly (Aim 3). As the scaffold and its constituents are increasingly understood to play important roles in human health and disease, such tools will not only enable further research on the scaffold but will also allow for its pharmacological manipulation in clinical contexts. Dysregulation of scaffold components such as the condensins, for instance, has been implicated in a growing number of malignancies, where they contribute to a particular form of genome instability known as chromosome instability. Genome instability is a key factor in the evolution of cancer cells, facilitating their escape from immune clearance and their acquisition of therapeutic resistance. By suppressing a pathway leading to chromosome instability, modulators of condensins (and other scaffold components) may act to limit the evolutionary potential of cancer cells.

项目摘要 有丝分裂染色体形成对于真核生物中遗传信息的传播至关重要。 分散的相间染色质转化为标志性的X形中期染色体 涉及三个主要事件：中央轴的形成（染色体“支架”），纵向 收缩和凝结。提出了合理的理论来解释后两个事件， 收缩是通过染色质环的扩展而发生的，并通过 染色体材料的体积相变。相比之下，关于构成知之甚少 有丝分裂支架及其存在一直是引起考虑争议的根源。直接的 脚手架存在的证据最近来自对中央丝的观察 受控膨胀的天然有丝分裂染色体。可以解放这种细丝， 完整的染色体限制在仔细核溶解中，为进一步研究提供了基础。 该建议旨在阐明有丝分裂染色体支架的基本原理，包括其 分子组成（AIM 1），其三维结构（AIM 2）及其与 染色质包围它（目标1和2）。获得的信息将提供全球视图 有丝分裂染色体的核心，解释其成分如何组装成介质比例的结构，以及该结构如何以一种确保其忠实和忠实和的方式组织基因组 有效分布。获得的知识将使对管理脚手架组装和拆卸的机制进行更详细的研究，以及其与其他蜂窝的相互作用的性质 成分（例如，染色质，动力学）。 该提案还旨在开发脚手架装配的化学调节剂（AIM 3）。作为 脚手架及其构成越来越理解，在人类健康中起重要作用， 疾病，这样的工具不仅可以对脚手架进行进一步的研究，而且还可以在临床背景下进行药物操纵。例如，在越来越多的恶性肿瘤中暗示了脚手架成分的失调，例如冷凝剂 特定形式的基因组不稳定性称为染色体不稳定性。基因组不稳定性是关键 癌细胞演变的因素，支持它们从免疫清除率逃脱并获得热阻力。通过抑制导致染色体不稳定性的途径，调节剂 冷凝蛋白（和其他支架成分）的作用可能会限制癌症的进化潜力 细胞。