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

项目概要/摘要 这是斯坦福大学医学讲师约书亚格鲁伯博士的K 08申请表 大学Gruber博士希望将自己定位为代谢物研究前沿的临床科学家， 表观遗传学的串扰与建立新的药物靶点，为患者的早期和长期目标， 晚期恶性肿瘤该K 08奖项将为Gruber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（HAT 1）依赖性恶性肿瘤; 2）机械表征潜在的HAT 1激活剂， 抑制剂; 3）确定膳食纤维衍生的丙酸酯如何修饰染色质的机制。博士 Gruber将由质谱方法方面的知名专家Michael Snyder博士指导 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 委员会成员包括斯坦福大学化学与系统生物学教授James Chen博士， 化学生物学方面;马克·史密斯博士，药物化学知识中心主任; 博士斯坦福大学代谢健康中心的科学主任凯文·孔特雷普伊斯（Kevin Contrepois）提供了大量的 光谱学培训;和Zena Werb，解剖学教授，加州旧金山弗朗西斯科， 就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代谢相结合，以确保有足够的营养物质来提供能量。 细胞分裂分子代谢物传感器允许细胞对营养可用性的变化做出反应。 乙酰辅酶A是生物合成过程、信号传导和表观遗传学的关键代谢物。然而，在这方面， 乙酸盐和其它含酰基代谢物的代谢物传感器知之甚少。因此，我们认为， 对乙酰-co-A传感的更好理解可能有助于开发新的方法 诊断、治疗或预防恶性肿瘤。格鲁伯博士发现了组蛋白乙酰转移酶HAT 1 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 HAT 1代谢物传感途径的特性，Gruber博士计划了一个详细的分子 研究人类肿瘤中的HAT 1依赖性，以了解 使HAT 1成为潜在的抗癌药物靶点（目的1）。为了提高操纵HAT 1的能力， 催化活性，Gruber博士筛选了小分子化学活化剂和抑制剂， 将进行生物化学表征（目标2）。最后，他计划定义HAT 1 将短链脂肪酸并入染色质（aim 3）。这项研究将提供科学的 基金会和必要的职业培训，以导致一个独立的学术研究职位博士。 格鲁伯与R 01级资金的预期结束的K奖期间。

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.