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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：
10054925
负责人：
JOSHUA JAMES GRUBER
金额：
$ 16.39万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-08 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054925
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.

项目总结/文摘