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

通过 HAT1 乙酰转移酶作为抗癌靶标进行代谢传感

基本信息

批准号：
10439267
负责人：
JOSHUA JAMES GRUBER
金额：
$ 16.39万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10439267
关键词：
Acetates Acetyl Coenzyme A Acetyltransferase Affect Amino Acids Anatomy Antineoplastic Agents Award Basic Science Binding Biochemical Biological Assay Biology Breast Breast Epithelial Cells California Cancer Biology Cancer Cell Growth Cell Culture Techniques Cell Cycle Cell Line Cell Nucleus Cell Proliferation Cell division Cells Chemicals Chromatin Clinical Oncology Complement Coupled Critical Pathways Data Dependence Development Diagnosis Diet Dietary Fiber Disease Drug Targeting Ensure Enteral Enzymes Epigenetic Process Experimental Models Fatty acid glycerol esters Fiber Foundations Funding Gastrointestinal tract structure Gene Expression Glucose Goals Growth HAT1 gene Hand Health Histones Human Impairment Intake Investigation K-Series Research Career Programs Kidney Knowledge Laboratories Lead Link Malignant - descriptor Malignant Neoplasms Mass Spectrum Analysis Medical Medicine Mentors Metabolic Metabolism Modification Molecular Multienzyme Complexes Mutation Neoplasms Nuclear Nuclear Import Nutrient Outcome Oxygen Pathway interactions Patients Pharmaceutical Chemistry Physicians Positioning Attribute Post-Translational Protein Processing Process Property Propionates Proteomics Reaction Research Research Personnel Research Proposals Role San Francisco Scientist Series Signal Transduction Site Systems Biology Testing Tissues Training Universities Volatile Fatty Acids Work acyl group adverse outcome anti-cancer base cancer cell cancer therapy career career development chromatin modification cofactor combat detection of nutrient epigenetic regulation expectation experience glucose metabolism glucose sensor histone acetyltransferase improved inhibitor/antagonist instructor malignant breast neoplasm mortality risk mouse model new therapeutic target novel novel strategies novel therapeutics nutrient metabolism prevent professor programs response sensor small molecule success tumor tumor growth tumor metabolism tumorigenesis

项目摘要

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.

项目摘要/摘要这是斯坦福大学医学讲师Joshua Gruber博士的K08的申请大学。格鲁伯博士希望将自己确立为临床医生，位于代谢物的最前沿表观遗传学串扰，其长期目标是为早期和早期患者建立新的药物靶标高级舞台恶性肿瘤。该K08奖将为Gruber博士提供支持，以实现以下内容职业发展目标：1）确定驱动组蛋白乙酰转移酶的分子机制 1（HAT1）依赖性恶性肿瘤； 2）机械特征潜在的HAT1激活剂和抑制剂； 3）确定饮食纤维衍生的丙酸如何修饰染色质的机制。博士 Gruber将由质谱法专家Michael Snyder博士指导包括蛋白质组学和代谢产物定量。 Gruber博士将由Calvin Kuo博士共同征收癌症生物学和营养代谢的专家。格鲁伯博士已经建立了指导委员会包括斯坦福大学化学与系统生物学教授詹姆斯·陈（James Chen）博士化学生物学方面；药物化学知识中心主任马克·史密斯（Mark Smith）博士；斯坦福代谢健康中心科学主任凯文·福雷斯（Kevin Contrepois）博士，提供群众光谱训练；加州大学旧金山分校解剖学教授Zena Werb 关于肿瘤发生和乳腺癌生物学实验模型的建议。癌细胞的生长与营养代谢相关，以确保存在足够的营养素以燃料细胞分裂。分子代谢产物传感器使细胞能够应对养分可用性的变化。乙酰-CO-A是生物合成过程，信号传导和表观遗传学的关键代谢产物。然而，醋酸盐和其他含酰基的代谢产物的代谢产物传感器知之甚少。所以，对乙酰基-CO-A传感的了解可以提高新方法的发展诊断，治疗或防止恶性肿瘤。 Gruber博士确定了组蛋白乙酰转移酶HAT1 作为乙酰基-CO-A和含酰基的短链脂肪酸的潜在传感器。确定可剥削的 HAT1代谢物感应途径的特性，Gruber博士计划了一个详细的分子调查HAT1依赖性人类肿瘤的依赖性，以了解对特性的理解使HAT1成为潜在的抗癌药物目标（AIM 1）。提高操纵HAT1的能力1 催化活性，Gruber博士筛选了小分子化学激活剂和抑制剂，它们将是生化特征的（AIM 2）。最后，他计划定义hat1的机制将短链脂肪酸掺入染色质（AIM 3）。这项研究将提供科学基金会和基本职业培训，导致博士的独立学术研究职位格鲁伯（Gruber）期望在K奖颁奖时期结束时获得R01级资金。