Molecular Buffering of Replication in Yeast

描述：(申请人提供)本建议书旨在提供 约翰·哈特曼拥有科学专长和成功的职业发展 在学术医学和基础科学方面。哈特曼博士已经完成了 他在华盛顿大学获得血液学奖学金的临床年份， 目前是弗雷德·哈钦森癌症研究所的第二年研究员 在他的导师Lee Hartwell和Maynard Olson的指导下，他在研究中心工作。 在接下来的五年里，哈特曼博士计划继续他对 酵母中DNA复制装置的分子缓冲。通过这些 研究，哈特曼博士的目标是对 癌症。他将使用新的方法在酵母中进行全基因组分析 为了更详细地了解维持复制的分子途径 Fidelity，特别关注基因变异对这些 小路。哈特曼博士将攻读与癌症生物学和 对复杂生物性状的分析以进一步实现他的科学研究 目标。FHCRC有许多有共同兴趣的教职员工，他们都参与了 在相关研究中。因此，已经组建了一个咨询委员会，以 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基因 多样性，因为它与健康和疾病有关，这是倡议之一 人类基因组计划的一部分。开始分析所需的研究工具 这样的生物复杂性目前已经存在，并且正在迅速发展中。 全球对遗传变异和分子间相互作用的认识 动态平衡是理解人类遗传结构的基础 复杂的特征，如癌症。这项提议是结合使用， 四环素调控的基因表达与4000多株单倍体酵母 缺失菌株全面系统鉴定所有非霍乱弧菌 能够缓冲复制压力的基本基因。如此详细的 目前只能在同基因酵母中进行分析，但它将提供 研究自然发生的基因影响的科学基础 人类复制保真度的变异。在这五年中 研究，哈特曼博士将深入了解细胞的分子原理 动态平衡，因为它们与复制保真度和癌症有关，他会 培养基因组分析的能力，这将在他的整个一生中很好地服务于他 独立研究科学家的职业生涯。

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.