Statistical Physics of DNA in Vivo

技术综述：该奖项支持理论、统计、物理和生物学之间的跨学科研究和教育。材料研究司和分子和细胞生物学司为这一奖项提供了资金。活细胞中的生物物理实验提供了生命过程如何在空间和时间上协调的定量描述。荧光显微镜、定量聚合酶链式反应、DNA芯片、荧光相关光谱和许多其他现代细胞和分子生物学技术正越来越有规律地被用于检测病毒感染、基因表达的调节、有丝分裂和间期染色体的结构和动力学、细胞运动以及分子马达的自组装。这些实验通常是定量的，提供了与生命过程相关的长度、时间和能量尺度的信息。与此同时，对纯化成分的体外实验提供了一幅与自然环境分离时相同过程的同样定量的图景。为组织体内生物物理实验提供的大量定量数据，并将这些数据与体外研究的结果相一致，PI制定了一个实用的理论框架。特别是，PI寻求建立活细胞中DNA和染色体结构的定量模型，并了解DNA的物理属性如何在转录、复制、重组和DNA损伤修复中发挥作用。聚合物的统计物理模型将用于构建体内DNA和染色质的有效模型。PI致力于解决的中心问题是：细胞内部的复杂性在多大程度上可以通过几个参数来描述？例如，在酵母的间期染色体的情况下，它们的结构和动力学将从限制在核内并沿着核外围的不同位置拴在一起的聚合物的观点来考虑。将理论计算结果与荧光实验结果进行比较，将得到间期染色体在体内的有效轮廓长度和持续长度。PI的合作使得对将被开发的中心理论思想的实验测试成为可能。在三个实验实验室中，物理研究生将与生物学专业的学生紧密合作，共同解决这项建议中概述的问题，从而创造一个能够促进跨学科研究蓬勃发展的智力环境。拟议的研究将与物理和生物相结合的多项教学举措紧密结合。这些是由国际和平研究所发起的对布兰代斯生物物理专业课程的进一步发展，以及完成国际和平研究所一直与合作者共同编写的一本关于“细胞的物理生物学”的教科书。PI正在参加为期四个月的研究轮换，这是布兰代斯生命科学一年级研究生的必修课。与PI进行轮换的学生将在物理学家实践的定量建模方面获得宝贵的经验，他们可以将这些经验应用于他们的论文工作和以后的生物医学研究生涯。非技术总结：该奖项支持理论统计物理和生物学交界处的跨学科研究和教育。材料研究司和分子和细胞生物学司为该奖项提供了资金。随着新实验技术的出现，生物系统的定量数据出现了字面上的爆炸性增长，有可能提供对生命过程的洞察。物理科学能够为理解这些数据做出重大贡献。该奖项支持这样的研究。PI将应用统计物理学来开发活细胞中DNA和染色体结构的定量模型，目的是更好地了解DNA的物理属性在涉及DNA的细胞过程中所起的作用，如转录、复制、重组和DNA损伤修复。这项研究将探讨简化模型在多大程度上能够捕捉到DNA在各种细胞过程中的基本物理过程。在三个实验实验室中，物理研究生将与生物学专业的学生紧密合作，共同解决这项建议中概述的问题，从而创造一个能够促进跨学科研究蓬勃发展的智力环境。拟议的研究将与物理和生物相结合的多项教学举措紧密结合。这些是由国际和平研究所发起的对布兰代斯生物物理专业课程的进一步发展，以及完成国际和平研究所一直与合作者共同编写的一本关于“细胞的物理生物学”的教科书。PI正在参加为期四个月的研究轮换，这是布兰代斯生命科学一年级研究生的必修课。与PI一起轮换的学生将获得物理学家实践的定量建模方面的宝贵经验，他们可以将这些经验应用到他们的论文工作中，以及后来作为生物医学研究人员的职业生涯中。

TECHNICAL SUMMARY:This award supports interdisciplinary research and education at the interface of theoretical statistical physics and biology. The Division of Materials Research and the Division of Molecular and Cellular Biology contribute funding to this award.Biophysical experiments in living cells provide a quantitative description of how the processes of life are orchestrated in space and time. Fluorescence microscopy, quantitative PCR, DNA chips, fluorescence correlation spectroscopy, and many other modern techniques of cellular and molecular biology are being used with increasing regularity to examine viral infection, regulation of gene expression, structure and dynamics of mitotic and interphase chromosomes, cell motility, and the self-assembly of molecular motors. These experiments are often quantitative in nature providing information about the length, time, and energy scales associated with life's processes. At the same time in vitro experiments on purified components are providing an equally quantitative picture of the same processes when isolated from their natural surroundings. The PI to develop a practical theoretical framework for organizing the wealth of quantitative data provided by biophysical experiments in vivo and for reconciling this data with results from in vitro studies. In particular, the PI seeks to develop quantitative models of DNA and chromosome structure in living cells and to understand how physical attributes of DNA play out in transcription, replication, recombination and DNA damage repair.Statistical physics models of polymers will be used to construct effective models for DNA and chromatin in vivo. The central question that PI aims to address is: To what extent can the complexity of the cellular interior be described by a few parameters? For example, in the case of interphase chromosomes in yeast, their structure and dynamics will be considered from the point of view of a polymer confined to the nucleus and tethered at various locations along the nuclear periphery. Comparing the results of theoretical calculations with fluorescence experiments, will lead to the determination of the effective, in vivo, contour length and persistence length for interphase chromosomes. The PI's collaborations enable expermental tests of the central theoretical ideas that will be developed. Physics graduate students working with the PI on the problems outlined in this proposal will closely collaborate with biology students in the three experimental labs thus creating an intellectual environment in which interdisciplinary research will be able to flourish.The proposed research will be tightly coupled to a number of teaching initiatives at the interface of physics and biology. These are the further development of courses for the Biological Physics major at Brandeis, initiated by the PI, as well as completing a textbook on the "Physical Biology of the Cell", which the PI has been writing with collaborators. The PI is taking part in four-month long research rotations which are mandatory for first year graduate students in the Life Sciences at Brandeis. Students doing a rotation with the PI will gain valuable experience in quantitative modeling as practiced by physicists that they can apply in their thesis work and later in their careers as biomedical researchers.NON-TECHNICAL SUMMARY:This award supports interdisciplinary research and education at the interface of theoretical statistical physics and biology. The Division of Materials Research and the Division of Molecular and Cellular Biology contribute funding to this award.With the advent of new experimental techniques, there has been a literal explosion of quantitative data on biological systems with the potential to provide insight into the processes of life. The physical sciences are able to make significant contributions to understanding these data. This award supports such research. The PI will apply statistical physics to develop quantitative models of DNA and chromosome structure in living cells with an aim to better understand the role physical attributes of DNA play in cellular processes involving DNA, such as transcription, replication, recombination and DNA damage repair. The research will address the extent to which simplified models can capture the essential physical processes that underlie the function of DNA in various cellular processes. Physics graduate students working with the PI on the problems outlined in this proposal will closely collaborate with biology students in the three experimental labs thus creating an intellectual environment in which interdisciplinary research will be able to flourish.The proposed research will be tightly coupled to a number of teaching initiatives at the interface of physics and biology. These are the further development of courses for the Biological Physics major at Brandeis, initiated by the PI, as well as completing a textbook on the "Physical Biology of the Cell", which the PI has been writing with collaborators. The PI is taking part in four-month long research rotations which are mandatory for first year graduate students in the Life Sciences at Brandeis. Students doing a rotation with the PI will gain valuable experience in quantitative modeling as practiced by physicists that they can apply in their thesis work and later in their careers as biomedical researchers.