Identifying Regulators of Cellular Aging that can Prevent Alzheimer's Disease

识别可以预防阿尔茨海默病的细胞衰老调节因子

• 批准号: 10624244
• 负责人: Benjamin Jacob Doranz
• 金额: $ 8.9万
• 依托单位: INTEGRAL MOLECULAR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10624244
• 关键词: Abbreviations; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Antibodies; Astrocytes; Biological Assay; Biological Markers; Biological Models; Biological Products; Cell Aging; Cells; Cellular Stress; Chronic Disease; Clinical Trials; DNA Damage; DNA Methylation; DNA Repair; Disease; Drug Targeting; Engineering; Epigenetic Process; Future; Gene Expression; Generations; Genes; Genomic Instability; Health; Human; Internal Ribosome Entry Site; Libraries; Link; Longevity; Marketing; Membrane; Methods; Microglia; Mitochondria; Modeling; Molecular Conformation; Monitor; Nutritional; Outcome; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Plasmids; Prevention; Process; Proteins; Proteome; Reactive Oxygen Species; Reporter; Source; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Intervention; Transfection; Translating; Virus Receptors; Work; cell age; cell growth regulation; cell preparation; comorbidity; expression vector; gene product; gene therapy; healthspan; immune checkpoint; improved; lentivirally transduced; manufacture; metaplastic cell transformation; methylation biomarker; mitochondrial dysfunction; mouse model; new therapeutic target; oxidation; pharmacologic; phase 2 study; prevent; programs; proteostasis; stem cell biology; stem cells; targeted treatment; telomere; therapeutic target; timeline; transcription factor

ABSTRACT Aging is the leading risk factor for Alzheimer’s Disease (AD) and many other chronic diseases, with more than 6.5 million cases of AD in the US. Regulating or slowing cellular aging, particularly in microglia and astrocytes that regulate neuroimmunity, would have a major impact on the treatment of AD, but the proteins that control cellular aging processes are poorly understood. Cellular aging has been characterized into 9 “hallmarks” or phenotypes that define aged cells. Most hallmarks are a result of cellular stress, such as DNA damage and oxidation, and are inter-related in both their causes and outcomes. The cellular aging process is linked to dramatically altered gene expression, which is largely controlled by transcription factors (TFs). Longevity studies between species also suggest that TF activity can define the rate of aging. We hypothesize that TFs can modulate cellular aging and that identifying the TFs that play a role in aging processes will enable an entirely new generation of therapeutic targets with the potential to treat, delay, and possibly even prevent AD. The discovery of TFs that can improve the lifespan of patients would have a profound impact on the prevention and treatment of AD and many other diseases.

摘要 老龄化是阿尔茨海默病(AD)和许多其他慢性病的主要风险因素，有超过 美国有650万例AD病例。调节或减缓细胞衰老，特别是在小胶质细胞和星形胶质细胞中 调节神经免疫，将对AD的治疗产生重大影响，但控制 人们对细胞衰老过程知之甚少。细胞老化已被描述为9个“标志”或 定义老化细胞的表型。大多数特征是细胞压力的结果，如DNA损伤和 氧化，并在其原因和结果是相互关联的。细胞衰老过程与 基因表达显著改变，这在很大程度上是由转录因子(TF)控制的。长寿 物种间的研究还表明，转铁蛋白的活性可以定义衰老的速度。我们假设TFS 可以调节细胞衰老，识别在衰老过程中发挥作用的因子将使 具有治疗、延缓甚至可能预防阿尔茨海默病的潜力的全新一代治疗靶点。 可以延长患者寿命的TFS的发现将对预防产生深远的影响 以及治疗阿尔茨海默病和许多其他疾病。