Nuclear Architecture and Disease

核结构与疾病

• 批准号: 9343591
• 负责人: thomas a misteli
• 金额: $ 184.33万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9343591
• 关键词: Affect; Aging; Aging-Related Process; Architecture; Area; Behavior; Cell Nucleus; Cells; Chromosomal translocation; DNA; Defect; Development; Disease; Genome; Genome Mappings; Goals; Health; Image; Interphase Cell; Laboratories; Life; Malignant Neoplasms; Maps; Methods; Molecular; Normal Cell; Nuclear; Patients; Positioning Attribute; Premature aging syndrome; Process; Progeria; Role; Sampling; Software Tools; Syndrome; System; Time; Work; base; cancer cell; cancer diagnosis; genome analysis; imaging modality; in vivo; normal aging; novel; screening; tumor

The aim of the Misteli laboratory is to understand how genomes are organized in vivo and how this organization contributes to genome function in health and disease. We have made significant progress in several areas: We have extended our earlier efforts to develop imaging methods to visualize genome function in living cells. In particular, we have developed an experimental system which allows us for the first time to visualize the behavior of broken DNA regions in living cells. We have used this system to probe the mechanism by which cancer chromosome translocations occur in intact cells. We have also continued our ongoing work on exploring the spatial organization of the genome in the interphase cell nucleus. We have developed novel software tools to analyze spatial genome positioning and we have applied it to the analysis of genome organization differences in normal and cancer cells. We are applying these methods to the development of novel cancer diagnosis strategies. We have also developed high-throughput imaging approaches to map genome regions with high precision in a large number of samples allowing for systematic spatial mapping and implementation of screening approaches for discovery. Finally, we are exploring the molecular mechanisms of the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS), in particular as a means to uncover the process of aging-related tumor formation. We are exploring the mechanism by which higher order genome organization is lost in HGPS patient cells and we are investigating the molecular basis for the organismal defects in HGPS patients and during normal aging. We are also using HGPS to explore the molecular mechanisms of aging-associated cancer formation.

Misteli实验室的目的是了解基因组在体内是如何组织的，以及这种组织如何有助于基因组在健康和疾病中的功能。我们已经在几个领域取得了重大进展：我们已经扩展了我们早期的努力，开发成像方法，以可视化活细胞中的基因组功能。特别是，我们开发了一个实验系统，使我们能够第一次可视化活细胞中断裂DNA区域的行为。我们已经使用这个系统来探测癌症染色体易位在完整细胞中发生的机制。我们还继续我们正在进行的探索间期细胞核中基因组空间组织的工作。我们开发了新的软件工具来分析空间基因组定位，并将其应用于正常细胞和癌细胞基因组组织差异的分析。我们正在将这些方法应用于开发新的癌症诊断策略。我们还开发了高通量成像方法，在大量样品中以高精度绘制基因组区域，从而允许系统的空间映射和筛选方法的实施。最后，我们正在探索过早衰老疾病Hutchinson-Gilford早衰综合征（HGPS）的分子机制，特别是作为揭示衰老相关肿瘤形成过程的一种手段。我们正在探索高阶基因组组织在HGPS患者细胞中丢失的机制，我们正在研究HGPS患者和正常衰老过程中生物缺陷的分子基础。我们还使用HGPS来探索衰老相关癌症形成的分子机制。