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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

基本信息

批准号：
10481463
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
项目类别：
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/10481463
关键词：
3-Dimensional Address 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 Laboratories Literature Malignant Neoplasms Mass Spectrum Analysis Mentors Mentorship Metaphase Methods Mitotic Mitotic Chromosome Molecular Nature Neoplastic Processes Pathway interactions Pharmacology Phase Transition Physical condensation Play Positioning Attribute Procedures Protocols documentation RNA Polymerase II Research Research Personnel Resolution Role Scientist 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 professor scaffold sequencing platform small molecule small molecule inhibitor structural biology success targeted cancer therapy tenure track theories therapy resistant tool

项目摘要

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.

项目总结