Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients

评估阿尔茨海默病患者衰老和恢复活力的神经元的细胞老化

基本信息

批准号：
10522910
负责人：
FRED H GAGE
金额：
$ 116.96万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522910
关键词：
3-Dimensional Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Antineoplastic Agents Apolipoprotein E Astrocytes Autopsy Binding Biological Assay Biological Process Brain Buffers Cell Aging Cell Nucleus Cells Chemicals Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Coupling Cytoplasm Data Detection Disease Disease Marker Disease Progression Effectiveness Elderly Engineering Environment Epigenetic Process Etiology Fibroblasts Genetic Genomics Goals Human Incidence Individual Knowledge Lead Malignant Neoplasms Metabolic Mitotic Modeling Molecular Nerve Degeneration Nervous system structure Neuroglia Neuronal Dysfunction Neurons Nuclear Oncogenic Onset of illness Paraffin Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacology Protein Isoforms Proteins Proteomics Protocols documentation Pyruvate Kinase RNA Splicing Role Structure Testing Therapeutic Tissues Transgenes Transgenic Organisms Variant Warburg Effect abeta deposition age related age related neurodegeneration aged anticancer research base base editing cancer cell cellular pathology disease phenotype disorder control drug development drug discovery genome editing injured insight lipidomics metabolic abnormality assessment metabolomics multiple omics neuroinflammation neuronal metabolism novel novel strategies paracrine preservation programs senescence single-cell RNA sequencing spatial relationship targeted treatment tau Proteins transcriptome sequencing

项目摘要

SUMMARY Alzheimer’s disease (AD) affects over 50 million people worldwide. The vast majority of patients, AD develops sporadically in the absence of any known etiology other than advanced age. Despite the fact that AD has been studied for over a century, its pathogenesis is still not completely understood, and drugs that could stop or reverse the disease progression are not yet available. Similar to the age-dependent incidence of many cancers, AD onset is believed to be caused by multiple hits of environmental, genomic, and aging-related factors. To better understand the cellular and molecular interactions between human aging and AD pathogenesis, induced neurons (iNs) directly converted from AD patient fibroblasts offer unique possibilities to model and study the disease in a human age-equivalent neuronal model. The teams around Dr. Gage and Dr. Mertens have recently shown that direct conversion of human AD patient-derived fibroblasts into induced neurons (iNs) preserves signatures of cell aging and sporadic AD and allows for the detection of cellular pathologies and disease drivers. Neuronal hypo-maturity represents a fundamental AD-related cellular state in iNs, and the cancer-associated Pyruvate Kinase M2 (PKM2) splice variant emerged as a key player that compromises mature neuronal metabolism and neuronal identity. PKM2 promotes neuronal vulnerability and de-differentiation via metabolic changes in the cytoplasm, and via epigenetic processes in the nucleus, but the relative contribution of the two mechanisms remains elusive and might differ substantially between cancer cells and post-mitotic neurons. To understand PKM2 in AD, and to develop PKM-directed therapeutics, more knowledge regarding (1) the relationship between neuronal PKM2 and hallmarks of AD in the human brain, (2) the fundamental cell biological functions of PKM2 in aged human neurons, and (3) the crosstalk between PKM-compromised neurons and their glial environment is needed. This project will challenge the importance of shared pathogenic pathways between cancer and AD, and assess age-dependently compromised neurons in the context of AD. First, the team will study the relationship between cancer-related PKM2-positive neurons and AD pathology in the post-mortem human brain. Second, the mechanistic impact of PKM2 imbalance on the metabolic state and neuronal fate stability of patient-specific iNs will be assessed by transgene- and genome editing-based approaches. Third, pharmacological compounds from the cancer field as a basis for developing PKM2-targeted therapeutics for AD will be leveraged. Fourth, using a novel human iN-based three-dimensional multicellular model, the team will study neuron-astrocyte coupling in the context of metabolically challenged iNs and their metabolic crosstalk with human astrocytes. The ultimate goals of these four aims are to gain insight into the roles of the well- established cancer protein PKM2 in age-related neurodegeneration and to exploit this knowledge to develop therapeutic strategies against AD.

概括阿尔茨海默氏病（AD）影响了全球超过5000万人。绝大多数患者，广告在没有任何已知的病因学以外的其他病因的情况下，偶尔发展。尽管事实是广告已经研究了一个多世纪，其发病机理仍未完全了解停止或逆转疾病进展。类似于许多与年龄有关的事件癌症，AD发作被认为是由多个环境，基因组和衰老相关的多次命中引起的因素。更好地了解人衰老与AD之间的细胞和分子相互作用发病机理，诱导神经元（INS）直接从AD患者成纤维细胞转换为独特的可能性在人类年龄等效的神经元模型中模型和研究该疾病。 Gage博士和Mertens博士围绕的团队最近表明，人类广告的直接转换患者衍生的成纤维细胞诱导神经元（INS）保存细胞衰老和零星AD的特征，允许检测细胞病理和疾病驱动因素。神经元的性不符代表 INS中的基本与广告相关的细胞状态和癌症相关的丙酮酸激酶M2（PKM2）剪接变体是损害成熟神经元代谢和神经元身份的关键参与者。 PKM2 通过细胞质的代谢变化以及通过细胞核中的表观遗传过程，但是两种机制的相对贡献仍然难以捉摸，并且癌细胞和有丝分裂后神经元之间可能有很大差异。了解广告中的PKM2，然后开发PKM定向疗法，有关（1）神经元PKM2之间关系的更多知识（2）PKM2在人类脑中的基本细胞生物学功能神经元和（3）需要PKM症状神经元与其神经胶质环境之间的串扰。该项目将挑战癌症和AD之间共享致病途径的重要性，以及在AD的背景下评估依赖年龄依赖性的神经元。首先，团队将研究关系在验尸后人脑中与癌症相关的PKM2阳性神经元和AD病理学之间。第二， PKM2失衡对患者特异性的代谢状态和神经元脂肪稳定性的机械影响 INS将通过转换和基因组编辑的方法进行评估。第三，药物癌症领域的化合物是开发PKM2靶向AD疗法的基础杠杆。第四，使用基于三维多细胞模型的新型人类，团队将研究在代谢挑战的INS及其代谢串扰的背景下，神经元群体耦合人星形胶质细胞。这四个目标的最终目标是深入了解善良的角色建立了与年龄相关的神经变性的癌症蛋白PKM2，并利用这些知识发展针对AD的治疗策略。