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：
10656473
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/10656473
关键词：
Acetates Acetyl Coenzyme A Acetyltransferase Affect Amino Acids Anatomy Antineoplastic Agents Award Basic Science Binding Biochemical Biological Assay Biology 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 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 Knowledge Laboratories Link Malignant - descriptor Malignant Neoplasms Mass Spectrum Analysis Medical Medicine Mentors Metabolic Metabolism Modification Molecular Multienzyme Complexes Mutation Neoplasms Nuclear Nuclear Import Nutrient Nutrient availability Outcome Oxygen Pathway interactions Patients Pharmaceutical Chemistry Physicians Positioning Attribute Post-Translational Protein Processing Process Proliferating Property Propionates Proteomics Reaction Renal carcinoma Repression 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 cancer cell cancer therapy career career development chromatin modification cofactor combat detection of nutrient epigenetic regulation expectation experience glucose metabolism glucose sensor high-fat/low-fiber diet histone acetyltransferase improved inhibitor 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.

项目概要/摘要这是斯坦福大学医学讲师 Joshua Gruber 博士的 K08 申请大学。 Gruber 博士希望成为代谢物前沿的临床医生科学家。表观遗传学串扰的长期目标是为早期和晚期患者建立新的药物靶点晚期恶性肿瘤。该 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) 依赖性恶性肿瘤； 2) 机制表征潜在的 HAT1 激活剂和抑制剂； 3) 确定膳食纤维衍生的丙酸如何修饰染色质的机制。博士。格鲁伯将接受质谱方法领域知名专家 Michael Snyder 博士的指导包括蛋白质组学和代谢物定量。 Gruber 博士将由 Calvin Kuo 博士共同指导，癌症生物学和营养代谢专家。格鲁伯博士建立了一个指导包括斯坦福大学化学与系统生物学教授 James Chen 博士在内的委员会提供建议化学生物学方面；马克·史密斯博士，药物化学知识中心主任；斯坦福代谢健康中心科学主任 Kevin Contrepois 博士提供质量光谱测定培训；和 Zena Werb，加州大学旧金山分校解剖学教授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来提供能量细胞分裂。分子代谢物传感器允许细胞对营养物质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，乙酸盐和其他含酰基代谢物的代谢传感器知之甚少。所以，对乙酰辅酶 A 传感的更好理解可能有助于开发新方法诊断、治疗或预防恶性肿瘤。 Gruber 博士鉴定出组蛋白乙酰转移酶 HAT1 作为乙酰辅酶 A 和含酰基短链脂肪酸的潜在传感器。识别可利用的为了了解 HAT1 代谢物传感途径的特性，Gruber 博士计划了一项详细的分子研究对人类肿瘤中 HAT1 依赖性的研究，以了解 HAT1 依赖性的特性使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，其中将进行生化表征（目标 2）。最后，他计划定义 HAT1 的机制将短链脂肪酸纳入染色质（目标 3）。这项研究将提供科学依据为博士获得独立学术研究职位提供基础和必要的职业培训。 Gruber 期望在 K 奖励期结束时获得 R01 级资金。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rationally targeted anti-VISTA antibody that blockades the C-C' loop region can reverse VISTA immune suppression and remodel the immune microenvironment to potently inhibit tumor growth in an Fc independent manner.

DOI：
10.1136/jitc-2021-003382
发表时间：
2022-03
期刊：
Journal for immunotherapy of cancer
影响因子：
10.9
作者：
Thakkar D;Paliwal S;Dharmadhikari B;Guan S;Liu L;Kar S;Tulsian NK;Gruber JJ;DiMascio L;Paszkiewicz KH;Ingram PJ;D Boyd-Kirkup J
通讯作者：
D Boyd-Kirkup J

Acetyl-Click Screening Platform Identifies Small-Molecule Inhibitors of Histone Acetyltransferase 1 (HAT1).

DOI：
10.1021/acs.jmedchem.3c00039
发表时间：
2023-04
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
J. D. Gaddameedi;T. Chou;Benjamin S. Geller;A. Rangarajan;Tarun A Swaminathan;Danielle Dixon;Katherine Long;Caiden J Golder;V. A. Vuong;Selene Banuelos;R. Greenhouse;M. Snyder;Andrew M. Lipchik;J. Gruber
通讯作者：
J. D. Gaddameedi;T. Chou;Benjamin S. Geller;A. Rangarajan;Tarun A Swaminathan;Danielle Dixon;Katherine Long;Caiden J Golder;V. A. Vuong;Selene Banuelos;R. Greenhouse;M. Snyder;Andrew M. Lipchik;J. Gruber