Mechanisms of the Mlx and Max Transcriptional Network in Aging

Mlx 和 Max 转录网络在衰老中的机制

• 批准号: 8694143
• 负责人: Andrew Vaughn Samuelson
• 金额: $ 32.76万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694143
• 关键词: Age; Aging; Aging-Related Process; Biology; Caenorhabditis elegans; Carbohydrates; Cell Aging; Cells; ChIP-seq; Complex; Coupling; Data; Development; Diabetes Mellitus; Disease; Elderly; Enzymes; Family; Functional disorder; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Programming; Genetic Transcription; Genomics; Glucose Intolerance; Goals; Health; Homeostasis; Homologous Gene; Human; Insulin; Insulin Resistance; Intervention; Investigation; Light; Link; Longevity; Longevity Pathway; Measurement; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic Pathway; Metabolism; Molecular; Molecular Biology; Mutation; Orthologous Gene; Output; Pathway interactions; Premature aging syndrome; Progeria; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Symptoms; Testing; Transcription Coactivator; Transcription Repressor/Corepressor; Williams Syndrome; Work; age related; carbohydrate metabolism; cell age; detection of nutrient; dietary restriction; factor C; functional genomics; improved; metabolomics; prevent; programs; public health relevance; research study; sensor; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): We have identified a functional role for Myc-related transcription factors of C. elegans in the process of aging. This family consists of two different heterodimers, the MDL and MML complexes, respectively, which have opposing roles in transcription and longevity control. The MML complex can extend lifespan and activate target gene transcription, whereas the MDL complex shortens lifespan and represses gene activity. These complexes interact genetically and molecularly with both insulin/IGF signaling and with dietary restriction. Thus, the Myc family of transcription factors represents a newly discovered convergence point for these central aging related pathways. We will investigate the molecular mechanisms by which the MML and MDL complexes influence longevity. Orthologous mammalian transcription factors have been linked to nutrient sensing, metabolic control, and disease. We will use metabolomics to discover the specific metabolic pathways that are altered by the MDL/MML complexes and link those metabolic changes to longevity using genetic and functional genomic approaches. The MML and MDL transcriptional complexes represent an evolutionarily conserved entity for coupling nutrient sensing, metabolism, and aging. Characterizing the newly discovered role of Myc transcription factors in the dynamic interplay between distinct longevity signals, in the experiments proposed here, may facilitate the development of rationale strategies for the treatment of age-associated disease and metabolic disorders (e.g. diabetes, glucose intolerance, and insulin resistance) to promote human health.

描述（由申请人提供）：我们已经鉴定了C. elegans在老化的过程中。该家族由两种不同的异二聚体组成，分别是MDL和MML复合物，它们在转录和寿命控制中具有相反的作用。MML复合物可以延长寿命并激活靶基因转录，而MDL复合物缩短寿命并抑制基因活性。这些复合物与胰岛素/IGF信号传导和饮食限制在遗传和分子上相互作用。因此，Myc家族的转录因子代表了这些中枢衰老相关通路的新发现的汇聚点。我们将研究MML和MDL复合物影响寿命的分子机制。直链哺乳动物转录因子与营养感知、代谢控制和疾病有关。我们将使用代谢组学来发现MDL/MML复合物改变的特定代谢途径，并使用遗传和功能基因组学方法将这些代谢变化与长寿联系起来。MML和MDL转录复合物代表了一个进化上保守的实体，用于耦合营养传感，代谢和衰老。在这里提出的实验中，表征新发现的Myc转录因子在不同长寿信号之间的动态相互作用中的作用，可能有助于开发用于治疗年龄相关疾病和代谢紊乱（例如糖尿病、葡萄糖耐受不良和胰岛素抵抗）以促进人类健康的合理策略。