Non-genetic Mutations in Aging Organisms

衰老生物体中的非基因突变

• 批准号: 8384452
• 负责人: Marc Vermulst
• 金额: $ 7.9万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384452
• 关键词: Affect; Age; Aging; Aging-Related Process; Alzheimer' s Disease; Bacteria; Biochemical; Biological; Biological Assay; Biology; Biology of Aging; Cell Aging; Cell physiology; Cells; Clinic; Congenital Disorders; Data; Disease; Event; Functional disorder; Gene Mutation; Genes; Genetic Code; Genetic Engineering; Genetic Screening; Genetic Transcription; Germ Lines; Goals; Health; Human; Life; Longevity; Measures; Medical; Modern Medicine; Molecular; Monitor; Mutagenesis; Mutation; Nerve Degeneration; Nucleic Acids; Organism; Parkinson Disease; Pathology; Pathway interactions; Physiology; Play; Prevention strategy; Proteins; Research Proposals; Resources; Role; Societies; Somatic Mutation; Techniques; Technology; Testing; Translations; Yeasts; age related; base; cell age; design; driving force; human disease; in vivo; malignant muscle neoplasm; non-genetic; novel; prevent; protein expression; research study; single molecule; tool; wasting

DESCRIPTION (provided by applicant): Genetic mutations play an important role in human aging and disease. By changing our genetic code, a mutation can disrupt the activity of a protein and permanently change the physiology of our cells. As a result, mutations can have a profound effect on human health. For instance, mutations in the germ line can result in congenital disorders, whereas somatic mutations contribute to cancer, muscle wasting and neuronal degeneration. An exciting new set of experiments now suggests that genetic mutations are not the only errors that contribute to human disease. In this research proposal, I will test the hypothesis that non-genetic mutations, i.e. mutations that occur during transcription and translation, also contribute to aging and age- related disease. To do this, I am developing highly sensitive technology that is capable of detecting these errors in vivo and I will use this tool to identify the parameters that modulate their error rates. Through genetic engineering I am also directly altering the error rate of transcription and translation to test whether this impacts celllar aging and age-related pathology. Finally, I will determine the molecular mechanisms by which non- genetic mutations impact cellular function, and identify the cellular pathways that are in place to prevent dysfunction. Together, these experiments may significantly deepen our understanding of aging and age-related pathology and help identify new targets for treatments or prevention strategies in the clinic. PUBLIC HEALTH RELEVANCE: Age-related diseases place an enormous strain on the medical and financial resources of Western society. Therefore, one of the most important challenges for modern medicine today will be to understand the molecular basis of the aging process. By understanding aging in greater detail, we may expose the driving force behind age-related diseases and thus discover new treatments or prevention strategies that are useful in the clinic. The primary goal of this research proposal is to understand how certain biological errors contribute to aging. These errors, which occur during protein expression, could play a role in various diseases, including Alzheimer and Parkinson disease. To achieve this goal, we will monitor these errors with highly sensitive techniques, record the lifespan of cells with increased error rates, and uncover the molecular underpinnings of our findings.

描述（由申请人提供）：基因突变在人类衰老和疾病中发挥着重要作用。通过改变我们的遗传密码，突变可以破坏蛋白质的活性并永久改变我们细胞的生理机能。因此，突变会对人类健康产生深远影响。例如，种系突变可能导致先天性疾病，而体细胞突变则导致癌症、肌肉萎缩和神经元变性。一组令人兴奋的新实验表明，基因突变并不是导致人类疾病的唯一错误。在本研究计划中，我将检验以下假设：非基因突变，即转录和翻译过程中发生的突变，也会导致衰老和年龄相关疾病。为此，我正在开发能够在体内检测这些错误的高度敏感的技术，并且我将使用该工具来识别调节其错误率的参数。通过基因工程，我还直接改变转录和翻译的错误率，以测试这是否会影响细胞衰老和与年龄相关的病理学。最后，我将确定非基因突变影响细胞功能的分子机制，并确定防止功能障碍的细胞途径。总之，这些实验可能会显着加深我们对衰老和与年龄相关的病理学的理解，并有助于确定临床治疗或预防策略的新目标。 公共卫生相关性：与年龄相关的疾病给西方社会的医疗和财政资源带来了巨大压力。因此，当今现代医学最重要的挑战之一将是了解衰老过程的分子基础。通过更详细地了解衰老，我们可以揭示与年龄相关的疾病背后的驱动力，从而发现可用于临床的新治疗或预防策略。这项研究计划的主要目标是了解某些生物错误如何导致衰老。这些在蛋白质表达过程中发生的错误可能在多种疾病中发挥作用，包括阿尔茨海默病和帕金森病。为了实现这一目标，我们将使用高度灵敏的技术监测这些错误，记录错误率增加的细胞寿命，并揭示我们研究结果的分子基础。