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 衰老是阿尔茨海默病（AD）和许多其他慢性疾病的主要风险因素， 6.5在美国有100万例AD病例。调节或减缓细胞衰老，特别是小胶质细胞和星形胶质细胞 调节神经免疫的蛋白质，将对AD的治疗产生重大影响，但是控制神经免疫的蛋白质， 细胞衰老过程知之甚少。细胞衰老被描述为9个“标志”或 定义衰老细胞的表型。大多数标志是细胞应激的结果，如DNA损伤和 氧化，并在其原因和结果相互关联。细胞衰老过程与 显著改变基因表达，这在很大程度上是由转录因子（TF）控制的。长寿 物种间的研究也表明TF活性可以决定衰老的速度。我们假设TF 可以调节细胞衰老，识别在衰老过程中起作用的TF将使我们能够在衰老过程中发挥作用。 全新一代的治疗靶点，具有治疗、延迟甚至可能预防AD的潜力。 发现可以延长患者寿命的TF将对预防疾病产生深远的影响。 以及治疗AD和许多其他疾病。