Non-genetic Mutations in Aging Organisms

衰老生物体中的非基因突变

• 批准号: 8726520
• 负责人: Marc Vermulst
• 金额: $ 24.9万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726520
• 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; abstracting; 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

Abstract 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 cellular 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.

抽象的 基因突变在人类衰老和疾病中起重要作用。通过更改我们的遗传密码， 突变会破坏蛋白质的活性，并永久改变我们细胞的生理学。因此， 突变会对人类健康产生深远的影响。例如，种系中的突变可能导致 先天性疾病，而体细胞突变会导致癌症，肌肉浪费和神经元 退化。现在，一组令人兴奋的新实验表明，遗传突变不是唯一的错误 这有助于人类疾病。在这项研究建议中，我将检验以下假设。 突变，即转录和翻译过程中发生的突变，也有助于衰老和年龄 相关疾病。为此，我正在开发能够检测到这些的高度敏感技术 体内错误和我将使用此工具来识别调节其错误率的参数。通过遗传 工程我还直接改变了转录和翻译的错误率，以测试这是否会影响 细胞衰老和与年龄有关的病理。最后，我将确定非分子机制 遗传突变会影响细胞功能，并确定已适当的细胞途径 功能障碍。这些实验总之可以显着加深我们对衰老和与年龄有关的理解 病理学并帮助确定诊所中治疗或预防策略的新目标。