Metabolite sensing through the HAT1 acetyltransferase as an anti-cancer target

项目摘要/摘要 这是斯坦福大学医学讲师Joshua Gruber博士的K08申请 大学。格鲁伯博士希望确立自己作为临床医生和代谢物前沿科学家的地位。 表观遗传学串扰，长期目标是为早期和慢性前列腺癌患者建立新的药物靶点 晚期恶性肿瘤。这一K08奖项将为格鲁伯博士提供支持，以实现以下目标 职业发展目标：1)确定驱动组蛋白乙酰转移酶的分子机制 1(HAT1)依赖的恶性肿瘤；2)潜在的HAT1激活物的机械特征和 抑制物；3)确定膳食纤维衍生的丙酸如何改变染色质的机制。Dr。 格鲁伯将得到迈克尔·斯奈德博士的指导，他是一位在质谱学方法方面公认的专家 包括蛋白质组学和代谢物定量。格鲁伯博士将由卡尔文·郭博士共同指导， 癌症生物学和营养代谢方面的专家。格鲁伯博士已经建立了一个指导 包括斯坦福大学化学和系统生物学教授James Chen博士在内的委员会将就 药物化学知识中心主任马克·史密斯博士； 斯坦福新陈代谢健康中心科学主任Kevin Contrepois博士提供质量 以及加州大学旧金山分校解剖学教授Zena Werb 对肿瘤发生和乳腺癌生物学的实验模型提供建议。 癌细胞的生长与营养新陈代谢有关，以确保有足够的营养物质提供燃料。 细胞分裂。分子代谢物传感器允许细胞对营养可获得性的变化做出反应。 乙酰辅酶A是生物合成、信号转导和表观遗传学的重要代谢物。然而， 醋酸酯和其他含酰基代谢物的代谢物感受器知之甚少。因此， 对乙酰辅酶A感觉的更好的理解可能有助于开发新的方法 诊断、治疗或预防恶性肿瘤。格鲁伯博士已经确定了组蛋白乙酰转移酶HAT1 作为乙酰辅酶A和含酰基短链脂肪酸的潜在传感器。识别可利用的 关于HAT1代谢物感应通路的特性，格鲁伯博士计划了一个详细的分子 研究人类肿瘤中对HAT1的依赖，以提供对 使HAT1成为潜在的抗癌药物靶点(目标1)。提高操纵HAT1的能力 催化活性，格鲁伯博士筛选了小分子化学激活剂和抑制剂，它们 将具有生物化学特征(目标2)。最后，他计划定义HAT1通过哪些机制 将短链脂肪酸结合到染色质中(目标3)。这项研究将为我们提供科学的 基础和基本的职业培训，使博士获得一个独立的学术研究职位。 格鲁伯希望在K奖励期结束时获得R01级资金。

PROJECT SUMMARY/ABSTRACT This is an application for a K08 for Dr. Joshua Gruber, an Instructor of Medicine at Stanford University. Dr. Gruber wishes to establish himself as a clinician-scientist at the forefront of metabolite- epigenetics crosstalk with a long-term goal of establishing novel drug targets for patients with early and advanced stage malignancies. This K08 award will provide Dr. Gruber support to achieve the following goals for career development: 1) Determine molecular mechanisms that drive histone acetyltransferase 1 (HAT1)-dependent malignancies; 2) Mechanistically characterize potential HAT1 activators and inhibitors; 3) Identify mechanisms of how dietary fiber-derived propionate modifies chromatin. Dr. Gruber will be mentored by Dr. Michael Snyder, an established expert in mass spectrometry approaches including proteomics and metabolite quantitation. Dr. Gruber will be co-mentored by Dr. Calvin Kuo, an expert in cancer biology and nutrient metabolism. Dr. Gruber has established a mentoring committee including Dr. James Chen, Stanford Professor of Chemical and Systems biology to advise on aspects of chemical biology; Dr. Mark Smith, director of the Medicinal Chemistry Knowledge Center; Dr. Kevin Contrepois, Scientific Director of the Stanford Metabolic Health Center, to provide mass spectrometry training; and Zena Werb, Professor of Anatomy, University of California San Francisco to advise on experimental models of tumorigenesis and breast cancer biology. Cancer cell growth is coupled to nutrient metabolism to ensure adequate nutrients exist to fuel cell division. Molecular metabolite sensors allow for cells to respond to changes in nutrient availability. Acetyl-co-A is a critical metabolite for biosynthetic processes, signaling and epigenetics. However, metabolite sensors of acetate and other acyl-containing metabolites are poorly understood. Therefore, an improved understanding of acetyl-co-A sensing may allow for the development of novel approaches to diagnose, treat or prevent malignancy. Dr. Gruber has identified the histone acetyltransferase HAT1 as a potential sensor of acetyl-co-A and acyl-containing short chain fatty acids. To identify exploitable properties of the HAT1 metabolite-sensing pathway, Dr. Gruber plans a detailed molecular investigation of HAT1-dependency in human tumors to provide an understanding of the properties that make HAT1 a potential anti-cancer drug target (aim 1). To advance the ability to manipulate HAT1 catalytic activity, Dr. Gruber has screened for small molecule chemical activators and inhibitors, which will be biochemically characterized (aim 2). Finally, he plans to define mechanisms by which HAT1 incorporates short-chain fatty acids to chromatin (aim 3). This research will provide scientific foundations and essential career training to lead to an independent academic research position for Dr. Gruber with the expectation of R01-level funding by the conclusion of the K award period.