Sirtuins and Cancer

Sirtuins 与癌症

基本信息

批准号：
10646361
负责人：
MARCIA HAIGIS
金额：
$ 56.23万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646361
关键词：
Adenosine Diphosphate Ribose Animals Bar Codes Biochemical Biochemistry Biological Assay Biology Cancer Etiology Carcinoma Cell Cycle Cell Proliferation Cell Survival Cells Cessation of life Chemicals Chemoresistance Colonic Neoplasms Colorectal Cancer Data Development Diagnostic Procedure Disease Outcome Enzymes Generations Genetic Genetically Engineered Mouse Genome Stability Genotoxic Stress Glutamine Goals Growth Human Hyperplasia Image Immunohistochemistry Intestinal Cancer Intestines Knowledge Malignant Neoplasms Maps Mass Spectrum Analysis Mediating Metabolic Metabolism Methods Mitochondria Modeling Molecular Nucleotide Biosynthesis Nucleotide Metabolism Alteration Nucleotides Oncogenic Organoids PIK3CA gene Pathway interactions Patients Phenotype Physiological Precision therapeutics Proliferating Protein Family Proteins Recycling Regulation Repression Resistance Resolution Role Signal Pathway Signal Transduction Sirtuins Survival Rate System Technology Testing Tumor Burden Work Xenograft Model biological adaptation to stress cancer cell cancer survival cell growth chemotherapy clinically relevant colorectal cancer progression experimental study improved in vivo in vivo Model innovation insight intestinal epithelium mitochondrial metabolism mouse model novel novel diagnostics novel therapeutic intervention nucleotide metabolism patient derived xenograft model physiologic model refractory cancer resistance mechanism response standard of care success targeted treatment tumor tumor metabolism tumor progression tumorigenesis

项目摘要

Project Summary Colorectal cancer (CRC) is the second leading cause of cancer-related death in the US, with a 5-year survival rate of only 60%. The poor disease outcome associated with CRC highlights an urgent need to understand the cellular mechanisms that influence initiation and progression of CRC. Several of the well-known genetic drivers of CRC such as KRas and PIK3CA are dominant regulators of metabolic reprogramming during cancer progression. Altered tumor metabolism facilitates generation of molecules important for cell growth, signaling, and survival; yet, our knowledge of the precise mechanisms that regulate metabolism and survival in chemotherapy resistant CRC remains incomplete. One family of proteins important in coordinating metabolism with cellular survival and stress responses is the NAD+-dependent sirtuin superfamily. Our preliminary data demonstrate that the loss of a mitochondrial localized sirtuin, SIRT4, occurs in CRC and results in the reprogramming of nucleotide biosynthesis to shift metabolites away from salvage nucleotide metabolism and upregulate de novo nucleotide biosynthesis. We hypothesize this metabolic switch contributes to increased CRC cell proliferation and resistance to chemotherapy. Our proposal will test this hypothesis in two complementary, but independent Aims. First, using a biochemical approach, Aim 1 will examine the mechanism by which SIRT4-mediated metabolic reprogramming increases cell proliferation by examining SIRT4 activity and substrates. We will also examine the role of the metabolic by-products downstream of SIRT4-mediated activity. Next, Aim 2 will test the consequence of clinically relevant SIRT4 loss in physiological models of CRC using organoids, novel genetically engineered mouse models, and patient derived xenograft (PDX) models. Finally, we will examine the consequences of SIRT4 loss on CRC metabolism and chemotherapy resistance in vivo. This project will provide an unprecedented map of metabolic reprogramming in CRC at a single cell level and improve understanding of how CRC metabolism changes in the context of chemotherapy resistance, opening the door for development of novel therapeutic strategies that leverage mitochondrial metabolism to treat chemotherapy resistant cancers.

项目摘要结直肠癌（CRC）是美国与癌症相关死亡的第二大原因，有5年存活率仅为60％。与CRC相关的疾病结果不佳，强调了迫切需要了解影响CRC开始和进展的细胞机制。几个众所周知的CRC的遗传驱动因素，例如KRAS和PIK3CA是代谢的主要调节剂在癌症进展过程中重新编程。改变肿瘤代谢有助于产生分子对细胞生长，信号传导和生存重要；但是，我们对确切的知识调节化学疗法CRC中代谢和存活的机制仍然不完整。一个蛋白质家族对于与细胞存活和应力反应协调代谢重要是NAD+依赖性的Sirtuin超家族。我们的初步数据表明，损失线粒体局部sirtuin，sirt4发生在CRC中，导致核苷酸重编程生物合成将代谢物转移到挽救核苷酸代谢并上调从核苷酸生物合成。我们假设这种代谢开关有助于增加CRC细胞增殖和对化疗的抗性。我们的建议将在两个中检验这一假设互补，但独立目标。首先，使用生化方法，AIM 1将检查 SIRT4介导的代谢重编程的机制可以增加细胞的增殖检查SIRT4活动和底物。我们还将检查代谢副产品的作用 SIRT4介导的活动的下游。接下来，AIM 2将测试临床相关的结果 SIRT4使用类器官的CRC生理模型中的SIRT4损失，新型基因工程小鼠模型和患者衍生的异种移植（PDX）模型。最后，我们将研究 CRC代谢和体内化学疗法抗性的SIRT4损失。该项目将提供一个 CRC中的代谢重编程的前所未有的地图，并改善了解CRC代谢在化学疗法抗性的背景下如何变化，开放开发新型治疗策略的大门，该策略利用线粒体代谢治疗抗化疗癌。