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Biophysics of Nuclear Formation and Micronucleation

核形成和微成核的生物物理学

基本信息

批准号：
10220079
负责人：
Tae Yeon Yoo
金额：
$ 7.05万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220079
关键词：
3-Dimensional Binding Biological Assay Biology Biophysical Process Biophysics Cancer Diagnostics Cell Nucleus Cell division Cell-Free System Cells Chromosomes Complex Congresses Contracts DNA DNA Binding DNA Damage Data Dependence Development Diagnostic Distant Environment Eukaryotic Cell Failure Fiber Foundations Genomic Instability Glass Goals Higher Order Chromatin Structure Individual Interdisciplinary Study Investigation Kinetics Knowledge Light Malignant Neoplasms Mechanics Mediating Microscope Microscopy Mitosis Mitotic Molecular Morphology Nature Nuclear Nuclear Envelope Pattern Phosphorylation Polymers Prevention Process Property Regulation Role Rupture Structure System Systems Biology Techniques Testing Therapeutic Time Translational Research Work Xenopus barrier-to-autointegration factor base biophysical analysis biophysical properties cancer cell cancer therapy crosslink dimer egg human tissue insight live cell microscopy mathematical model medical schools microscopic imaging novel novel therapeutics polymerization prevent reconstitution skills systems research tissue/cell culture

项目摘要

Project Summary/Abstract The cell nucleus of higher eukaryotic cells undergoes a dynamic process of disassembly and reassembly during the open mitosis. Failing to reform a single nucleus encasing the entire set of chromosomes often results in small extranuclear bodies, referred to as micronuclei. Micronuclei are prone to irreversible rupture and catastrophic DNA damages, which has been largely implicated in cancer. Recent works have suggested that barrier-to-autointegration factor (BAF/BANF1) crosslinks DNA to a single mass, thereby guiding nuclear membranes to bridge across chromosomes. However, further investigation is necessary to understand detailed biophysical mechanism of action by which BAF mediates nuclear membranes. Previous studies and preliminary data led to the hypothesis of this study that BAF may form fiber-like structures, beyond simple dimers, that connect and congress distant chromosomes. The goal of the proposed study is to investigate this possibility and its implications in nuclear envelope formation. To this end, the first aim is to develop a biophysical assay using Xenopus egg extract and micro-patterned DNA to scrutinize the bridging of nuclear envelope across gaps between chromosomes, and quantitatively dissect the role of BAF complex during this process. In the next aim, 3D dynamics of the fiber-like structures of BAF during nuclear formation will be analyzed in living cells, using lattice light-sheet microscopy and molecular perturbation techniques. Finally, DNA binding and polymerization dynamics of BAF revealed in the extract system and living cells will be reconstituted in a simplest system of purified components to further investigate the biophysical basis. Consequently, the proposed study will offer the mechanistic insight into nuclear formation and micronucleation and establish the foundation for mathematical modeling of these processes. Furthermore, the results have the potential to expand our understanding of cancer micronuclei, thereby aiding in the development of novel cancer therapy and diagnostics. Conducting the proposed study, the applicant aims to deepen his expertise in quantitative biology and microscopy, while at the same time, expanding the breadth of his skills and intellectual horizon to reconstituted cell-free systems and translational research. This project will benefit from the highly interdisciplinary research environment of the Systems Biology department at Harvard Medical School along with the sponsor’s strong support.

项目总结/文摘