A Systems Approach to Targeting Innate Immunity in AD

我们在AMP-AD联盟中资助的U01项目的首要目标是确定治疗靶点 在先天免疫途径中。在上一个供资期间，我们取得了重大进展，满足了所有 我们U01的里程碑。我们已经在免疫系统中提名了多个靶点，这些靶点位于 验证的各个阶段。然而，我们理解上的主要差距阻碍了集体的转变 AMP-AD知识到有效的治疗靶点。尽管发现了许多受干扰的转录 网络，其中一些富含阿尔茨海默病(AD)风险基因，这些网络中的关键易处理目标是 没有明确识别和确认的。此外，观察到的转录变化是不是简单的 疾病的后果，或者实际上，在病理性级联反应中起作用，通常还没有确定。 最后，在大多数情况下，有利与不利的分子变化方向已经被提名 目标，还没有确定。为了克服这些知识差距，我们将i)利用我们的 现有数据和工具以及较大的AMP-AD联合体产生的数据和分析，二)产生 补充新数据，以及iii)应用创新的分析方法。值得注意的是，我们的表演能力 对照(无病理)、路径抗原(病理性衰老，淀粉样蛋白)、AD(tau，淀粉样蛋白)和 PSP(进行性核上性麻痹，tau)使框架能够识别起作用的治疗靶点。 在向AD的不同疾病阶段过渡。此外，两个大脑区域之间的比较 (TCX=在AD中受影响，CER=在AD中基本不受影响)以及AD和PSP之间的差异可以帮助区分 确认的分子变化可能是病理的原因或结果。在此续期申请中，我们 建议：一)提炼和基因验证治疗靶点二)确定分子机制和靶点 介导疾病从对照到路径抗原再到AD的转变III)确定药物靶向机制(S)IV 在相关模式中选择优先目标，v)继续与所有AMP-AD合作伙伴协作，以促进 联盟广泛的目标验证和vi)与更大的科学界公开分享我们的数据。这些 研究将包括对原始文件中确定的20多个免疫靶点进行建模研究的最后阶段 授予周期，目标是在选定的目标上做出坚定的去，不去，决定。这些研究将使我们能够i) 提供对拟议目标的作用机制的生物学洞察，并II)提供关于 需要改变才能获得治疗效果。确定推动从控制过渡到 淀粉样蛋白阳性，然后到tau病理和神经退行性变将使我们能够提出 在适当的疾病阶段操纵这些靶点的治疗方法的未来临床测试-增加 达到临床疗效的可能性，并避免昂贵的试剂测试，意在治疗人群 不太可能从中受益。

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.