Molecular Buffering of Replication in Yeast

产品说明： （申请人提供）本提案旨在提供 约翰·哈特曼凭借科学专业知识和职业发展取得成功 学术医学和基础科学。 哈特曼博士已经完成了 他在华盛顿大学血液学奖学金的临床一年， 在弗雷德·哈钦森癌症研究所做研究的第二年 研究中心的指导下，他的导师，李哈特韦尔和梅纳德奥尔森。 在接下来的五年里，哈特曼博士计划继续研究 酵母中DNA复制装置的分子缓冲。 由这些 研究，哈特曼博士的目的是获得新的见解的起始事件， 癌 他将采用新方法进行酵母全基因组分析 更详细地了解维持复制的分子途径 保真度，特别关注遗传变异对这些 途径。 哈特曼博士将承担与癌症生物学相关的课程， 分析复杂的生物特征，以进一步实现他的科学研究 目标. FHCRC有许多具有共同兴趣的教职员工，他们从事 在相关研究中。 因此，成立了一个咨询委员会， 促进哈特曼博士的研究和学术进步。 哈特曼博士的长期职业目标是更好地了解人类遗传 与健康和疾病相关的多样性，这是一项倡议， 人类基因组计划。 开始分析所需的研究工具 这种生物学复杂性目前是可获得的，且正在快速开发中。 遗传变异和分子生物学之间相互作用的全球评价 内稳态是理解遗传结构的基础， 复杂的特征，如癌症。 这项建议是结合使用， 四环素调控的基因表达和超过4000个单倍体酵母的集合 删除菌株，以全面和系统地鉴定所有非 能够缓冲复制压力的必需基因。 如此详细的 分析目前只可能在同基因酵母，但它将提供 研究自然发生的遗传影响的科学基础 人类复制保真度的变化。 在这五年里， 研究，哈特曼博士将深入了解细胞的分子原理 稳态，因为它们与复制保真度和癌症有关，他将 发展基因组分析的能力，这将有助于他在整个 作为一名独立的研究科学家。

DESCRIPTION: (provided by Applicant) This proposal is designed to provide John Hartman with the scientific expertise and career development for success in academic medicine and basic science. Dr. Hartman has completed the clinical year of his hematology fellowship at the University of Washington, and is in the second year of research fellowship at the Fred Hutchinson Cancer Research Center under guidance of his mentors, Lee Hartwell and Maynard Olson. During the next five years, Dr. Hartman plans to continue his studies of molecular buffering of the DNA replication apparatus in yeast. By these studies, Dr. Hartman aims to gain new insights into the initiating events in cancer. He will employ novel methodologies for genome-wide analysis in yeast to understand in more detail the molecular pathways that maintain replication fidelity, with a special focus on the impact of genetic variation on these pathways. Dr. Hartman will undertake coursework related to cancer biology and analysis of complex biologic traits to further attain his scientific research goals. FHCRC has many faculty members with shared interests, who are engaged in related studies. Accordingly, an advisory board has been assembled to facilitate Dr. Hartman's research and academic progress. Dr. Hartman's long-term career goal is to better understand human genetic diversity as it relates to health and disease, which is one of the initiatives of the human genome project. The research tools necessary to begin analyzing such biologic complexity are presently available and under rapid development. A global appreciation of the interplay between genetic variation and molecular homeostasis is fundamental to understanding the genetic architecture of complex traits, such as cancer. This proposal is to use, in combination, tetracycline-regulated gene expression and the set of over 4000 haploid yeast deletion strains to comprehensively and systematically identify all non- essential genes capable of buffering replication stress. Such a detailed analysis is currently possible only in isogenic yeast, but it will provide the scientific foundation to investigate the impact of naturally occurring genetic variation upon replication fidelity in humans. During the five years of this research, Dr. Hartman will gain insight into molecular principles of cellular homeostasis, as they relate to replication fidelity and cancer, and he will develop aptitude for genome analysis that will serve him well throughout his career as an independent research scientist.