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The regulation of cancer and aging by methionine

蛋氨酸对癌症和衰老的调节

基本信息

批准号：
10750559
负责人：
VINCENT L. CRYNS
金额：
$ 61.97万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750559
关键词：
4T1 Address Adult Affect Age Aging Amino Acids Anabolism Animal Cancer Model Animals Biological Breast Cancer Cell Breast Cancer Model Breast Carcinoma Cell Culture Techniques Cell model Cells DNA Methylation DNA Modification Methylases DNA Modification Process Dependence Development Diet Dietary Component Dietary Intervention Dietary Proteins Disease Ensure Epigenetic Process Frequencies Gene Expression Profiling Genetic Transcription Health Health Benefit High Prevalence Human Immunodeficient Mouse Inbred Strain Inbreeding Individual Integration Host Factors Intervention Knowledge Link Longevity Maintenance Malignant Neoplasms Mammary Neoplasms Maps Mediating Mediator Metabolic Metabolism Methionine Methionine Metabolism Pathway Modeling Molecular Morbidity - disease rate Mouse Strains Mus Neoplasm Metastasis Normal tissue morphology Pathology Pathway interactions Persons Phenotype Plants Play Population Prevention Process Property Protein Kinase Rattus Regulation Research Resistance Rodent Role S-Adenosylhomocysteine S-Adenosylmethionine Societies Techniques Testing Tumor Promotion Tumor Tissue Vegan Diet Work Xenograft procedure age effect age related aged anti-cancer anticancer research antitumor effect cancer initiation cancer therapy dietary dietary restriction epigenetic profiling epigenome experimental study genetic approach healthspan healthy aging histone methylation histone methyltransferase histone modification improved in vivo insight interest juvenile animal malignant breast neoplasm metabolic phenotype model organism mortality mouse model multidisciplinary mutant novel older women patient derived xenograft model pharmacologic prevent response self-renewal sensor stem tumor tumor growth tumor initiation tumor progression tumorigenesis

项目摘要

Project Summary Age-related diseases, including cancer, are the major causes of morbidity and mortality in Western society. While cancer in the genetically heterogeneous human population primarily occurs in the aged, cancer research to-date has primarily utilized young, inbred animals. As the effect of aging and host factors on cancer development and progression has grown increasingly evident, the limitations of this approach have become clear. Understanding how aging impacts cancer development, progression, and the response to interventions will provide mechanistic insights into the prevention and treatment of cancer as individuals grow older, and eventually will permit the development of new pharmacological approaches to this age-associated disease that will enable healthy aging. Here, we build on recent work by our team and others demonstrating that restricting dietary protein, or restriction of specific dietary amino acids, can extend the lifespan and healthspan of mice. We will utilize methionine restriction (MR), a dietary intervention that extends longevity and improves metabolic health in mice, and which in mouse xenograft studies has been shown to slow the progression of certain cancers, including breast cancer, the most common cancer in older women. Limitations of MR research to date include the fact that the effect of MR on healthspan is limited in scope, that the effects of MR have been studied only in a few young mouse strains, and that the cancer studies done to-date have exclusively relied on young hosts. Understanding how MR affects the healthspan, longevity, and natural development of breast cancer during the aging of genetically heterogeneous mice will provide valuable new insights into the potential application of MR-based interventions for the health, longevity and treatment of cancer in the genetically heterogeneous human population. We will use cutting edge techniques to isolate and characterize cancer initiating cells (CICs), examine how changes in levels of methionine and its metabolites affect the epigenome. We will use two breast tumor models to examine how host age impacts CICs, tumor growth and/or metastasis and the response to MR. Finally, we will determine the role of specific molecular sensors of methionine metabolites in the epigenetic and anti-cancer effects of MR during aging. The proposed work will address long- standing questions regarding the molecular mechanisms by which dietary components regulate healthy aging and cancer.

项目摘要在西方国家，与癌症有关的疾病，包括癌症，是发病率和死亡率的主要原因。社会虽然遗传异质性人群中的癌症主要发生在老年人中，但癌症迄今为止的研究主要利用幼小的近亲繁殖动物。由于衰老和宿主因素对癌症的影响发展和进步越来越明显，这种方法的局限性已经成为清楚了解衰老如何影响癌症的发展，进展和对干预措施的反应将为随着个体年龄的增长预防和治疗癌症提供机制性见解，最终将允许开发新的药理学方法来治疗这种年龄相关疾病，将使健康的老龄化。在这里，我们建立在我们的团队和其他人最近的工作基础上，证明限制膳食蛋白质，或限制特定的饮食氨基酸，可以延长小鼠的寿命和健康寿命。我们将利用蛋氨酸限制（MR），一种延长寿命和改善小鼠代谢健康的饮食干预，并且在小鼠异种移植研究中已显示其减缓某些癌症的进展，包括乳腺癌是老年妇女最常见的癌症。迄今为止，MR研究的局限性包括以下事实： MR对健康寿命的影响范围有限，仅在少数年轻人中研究了MR的影响小鼠品系，迄今为止所做的癌症研究完全依赖于年轻的宿主。了解MR如何影响乳腺癌的健康寿命、寿命和自然发展在遗传异质性小鼠的衰老过程中，基于MR的干预措施在遗传学领域的健康、长寿和癌症治疗的应用异质人群。我们将使用尖端技术来分离和描述癌症启动细胞（CIC），研究蛋氨酸及其代谢物水平的变化如何影响表观基因组。我们将使用两个乳腺肿瘤模型来研究宿主年龄如何影响CIC、肿瘤生长和/或转移最后，我们将确定蛋氨酸的特定分子传感器的作用代谢物的表观遗传和抗癌作用的MR在老化。这项工作将长期持续下去- 关于饮食成分调节健康衰老的分子机制的长期问题和癌症