A Systems Approach to Targeting Innate Immunity in AD

针对 AD 中先天免疫的系统方法

• 批准号: 10475289
• 负责人: NILUFER ERTEKIN-TANER
• 金额: $ 242.14万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475289
• 关键词: Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Biological; Biological Models; Brain; Brain region; Cerebellar Cortex; Collaborations; Communities; Data; Data Analyses; Disease; Drug Targeting; Economics; Elderly; Epigenetic Process; Equilibrium; Evaluation; Funding; Future; Generations; Genes; Genetic Transcription; Genetic study; Genotype; Goals; Grant; Immune Targeting; Immune system; Information Systems; Innate Immune System; Knowledge; Mediating; Medical; Medicine; Mining; Modeling; Molecular; Natural Immunity; Nerve Degeneration; Other Genetics; PLCG2 gene; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Patients; Phase; Play; Population; Pre-Clinical Model; Process; Progressive Supranuclear Palsy; Proteome; Recombinant adeno-associated virus (rAAV); Role; Slice; Study models; System; TREM2 gene; Tauopathies; Temporal Lobe; Testing; Therapeutic; Validation; antagonist; base; clinical efficacy; cohort; comparative; cost; data tools; genome-wide; human data; immune activation; in vivo; innovation; insight; member; mouse model; new therapeutic target; novel; novel therapeutic intervention; open data; pathological aging; research clinical testing; risk variant; tau Proteins; therapeutic evaluation; therapeutic target; transcription regulatory network; transcriptome; transcriptomics; whole genome

Our funded U01 project in the AMP-AD consortium had the overarching aim of identifying therapeutic targets within innate immunity pathways. In the previous funding period, we made significant progress and met all milestones of our U01. We have nominated multiple targets in the immune system, and these targets are at various stages of validation. Nevertheless, key gaps in our understanding impede transformation of the collective AMP-AD knowledge to validated therapeutic targets. Despite identification of numerous perturbed transcriptional networks, some enriched for Alzheimer's disease (AD) risk genes, key tractable targets in these networks are not unequivocally identified and validated. Further, whether the observed transcriptional changes are a simple consequence of disease or actually, play a role in the pathologic cascade has, typically, not been determined. Finally, the direction of molecular changes that is beneficial vs. detrimental has, in most cases of nominated targets, not been established. To overcome these gaps in knowledge, we will i) leverage unique aspects of our existing data and tools along with data and analyses generated by the larger AMP-AD consortia, ii) generate complementary new data, and iii) apply innovative analytic approaches. Notably, our ability to perform comparative analysis of control (no pathology), PathAg, (Pathologic Aging, amyloid+), AD (tau+, amyloid+) and PSP (progressive supranuclear palsy, tau+) enables a framework to identify therapeutic targets that play a role in the transition to different disease stages of AD. Further, comparisons between two brain regions (TCX=affected and CER=largely spared in AD) and between AD and PSP can help distinguish whether the molecular changes identified are likely a cause or consequence of pathology. In this renewal application, we propose to: i) refine and genetically validate therapeutic targets ii) identify molecular mechanisms and targets that mediate disease transition from control to PathAg to AD iii) define the drug target mechanism(s) iv) evaluate select prioritized targets in relevant models, v) continue the collaboration with all AMP-AD partners to promote consortium wide-target validation and vi) share our data openly with the larger scientific community. These studies will include the final phase of modeling studies for more than 20 immune targets identified in the original grant cycle with a goal of making firm go, no-go, decisions on select targets. These studies will enable us to i) provide biologic insight into the mechanism of action of the proposed targets and ii) inform on the direction of change needed for therapeutic benefit. Identification of key targets that drive the transition from control to amyloid positivity, and then to tau pathology and neurodegeneration will enable us to propose alignments of future clinical testing of therapeutics that manipulate these targets in appropriate disease stages-increasing the likelihood to achieve clinical efficacy and avoiding costly testing of an agent in an intent to treat population that is unlikely to benefit.

我们在AMP-AD财团中资助的U01项目的总体目的是确定治疗目标 在先天的免疫道路内。在上一个资金期间，我们取得了重大进展，并满足了所有 我们U01的里程碑。我们提名了免疫系统中的多个目标，这些目标是 验证的各个阶段。然而，我们的理解中的关键差距阻碍了集体的转变 AMP-AD知识是验证的治疗靶标。尽管鉴定了许多干扰转录 网络，有些人富含阿尔茨海默氏病（AD）风险基因，这些网络中的主要可拖动目标是 未明确识别和验证。此外，观察到的转录变化是否很简单 疾病的后果或实际上在病理级联反应中发挥作用，通常没有确定。 最后，在大多数提名的情况下 目标，未建立。为了克服这些知识的差距，我们将）利用我们的独特方面 现有的数据和工具以及较大的AMP-AD财团生成的数据和分析，ii）生成 互补的新数据和iii）采用创新的分析方法。值得注意的是，我们的表现能力 对照（无病理），Pathag（病理老化，淀粉样蛋白+），AD（TAU+，淀粉样蛋白+）和 PSP（渐进性上核麻痹，tau+）使一个框架能够识别出扮演角色的治疗靶标 在过渡到AD的不同疾病阶段。此外，两个大脑区域之间的比较 （TCX =受影响，CER =在AD中很大程度上幸免），并且在AD和PSP之间可以帮助区分是否存在 鉴定出的分子变化可能是病理的原因或结果。在此续签应用中，我们 提议：i）精炼和遗传验证治疗靶标ii）确定分子机制和靶标 介导从对照到Pathag到AD III的疾病过渡）定义药物靶机理（S）IV）评估 选择相关模型中的优先目标，v）继续与所有AMP-AD合作伙伴进行合作以促进 联盟广泛目标验证和vi）与更大的科学界公开共享我们的数据。这些 研究将包括针对原始鉴定的20多个免疫靶标建模研究的最后阶段 授予周期的目标是使公司对某些目标进行决策。这些研究将使我们进入我） 提供有关拟议目标作用机理的生物学洞察力，ii）有关 治疗益处所需的更改。识别驱动从控制到过渡到的关键目标 淀粉样蛋白的阳性，然后到tau病理学和神经变性将使我们能够提出一致性 在适当疾病阶段操纵这些靶标的治疗剂的未来临床测试， 实现临床疗效并避免对人群的代理人进行昂贵测试的可能性，以治疗人群 不太可能受益。