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.

项目概要结直肠癌 (CRC) 是美国癌症相关死亡的第二大原因，5 年发病率成活率只有60%。结直肠癌相关的不良疾病结果凸显了迫切需要了解影响 CRC 发生和进展的细胞机制。其中几个众所周知的 CRC 遗传驱动因素，例如 KRas 和 PIK3CA，是代谢的主要调节因子癌症进展期间的重编程。改变肿瘤代谢有利于产生对细胞生长、信号传导和生存很重要的分子；然而，我们对精确的知识调节化疗耐药结直肠癌代谢和生存的机制仍然不完整。在协调新陈代谢与细胞生存和应激反应方面发挥重要作用的一类蛋白质是NAD+依赖性sirtuin超家族。我们的初步数据表明，损失线粒体定位的 Sirtuin SIRT4 发生在 CRC 中并导致核苷酸重编程生物合成将代谢物从挽救核苷酸代谢中转移出来并从头上调核苷酸生物合成。我们假设这种代谢转换导致 CRC 细胞增加增殖和对化疗的耐药性。我们的提案将分两步检验这个假设互补但独立的目标。首先，目标 1 将使用生化方法检查 SIRT4介导的代谢重编程增加细胞增殖的机制检查 SIRT4 活性和底物。我们还将研究代谢副产物的作用 SIRT4 介导的活性的下游。接下来，目标 2 将测试临床相关的结果使用类器官、新型基因工程小鼠的 CRC 生理模型中 SIRT4 缺失模型和患者来源的异种移植（PDX）模型。最后，我们将检查以下后果： SIRT4 缺失对 CRC 代谢和体内化疗耐药性的影响。该项目将提供一个在单细胞水平上绘制出前所未有的结直肠癌代谢重编程图并改善了解 CRC 代谢在化疗耐药情况下如何变化，开启开发利用线粒体代谢进行治疗的新型治疗策略的大门化疗耐药的癌症。