CircuitATLAS：面向回路病靶点发现的系统神经科学知识图谱上的智能体推理
CircuitATLAS: Agentic reasoning over a systems neuroscience knowledge graph for target discovery in circuitopathies
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中文总结 AI 辅助
CircuitATLAS构建系统神经科学知识图谱与智能体框架，从疾病表型推理至分子控制点，发现ATP1A3为皮层兴奋性靶点并经体内实验验证，为回路病提供基于可调控节点的药物发现新范式。
中文摘要 AI 辅助
神经系统疾病的药物发现传统上聚焦于疾病所改变的分子。但导致病理的分子未必是逆转病理的最佳切入点。在此，我们探究哪些原本未改变的分子控制点可以被调动，以将病理神经回路恢复至功能状态。我们提出CircuitATLAS，一个基于溯源的系统神经科学知识图谱和智能体框架，用于回路病中的靶点发现。它构建了跨越疾病、表型、电生理、回路、脑区、细胞类型和分子效应物之间的文献衍生关系，同时刻意排除直接的疾病-基因和疾病-蛋白质边，以减少捷径推理。该图谱包含383万个节点和766万条边，其中包括531万条由大语言模型提取的关系，并整合了诸如人类细胞图谱（Human Cell Atlas）和新的多模态体内测量等结构化数据集。随后，我们引入一个智能体工作流，从可测量的疾病表型出发，通过其回路和细胞底物推理至分子干预、治疗可行性和临床约束。最后，我们引入一个人工监管的体内实验室在环（lab-in-the-loop）机制，将假设生成与实验迭代相连接。在该框架内，一个智能体提名ATP1A3（神经元α3 Na+/K+-ATP酶）作为皮层兴奋性的控制点；中间神经元限制性表达的ATP1A3消除了体内局灶性4-氨基吡啶挑战下的β和γ波段反应，随后该已验证靶点被带入一个结构引导的小分子运动，最终在一个明确测定中确定调节方向。因此，CircuitATLAS提供了一个框架，不仅基于疾病中分子层面的破坏，还基于可被控制以恢复回路功能的因素来发现治疗药物。
英文摘要
Drug discovery for neurological disease has traditionally centered on the molecules altered by disease. But the molecules that cause pathology are not necessarily the best points from which to reverse it. Here, we ask which otherwise unaltered molecular control points can be engaged to restore pathological neural circuits toward functional states. We present CircuitATLAS, a provenance-grounded systems-neuroscience knowledge graph and agentic framework for target discovery in circuitopathies. It structures literature-derived relationships across diseases, phenotypes, electrophysiology, circuits, brain regions, cell types and molecular effectors, while deliberately excluding direct disease-gene and disease-protein edges to reduce shortcut reasoning. The graph contains 3.83 million nodes and 7.66 million edges, including 5.31 million LLM-extracted relations, and incorporates structured datasets such as the Human Cell Atlas and new multimodal in vivo measurements. We then introduce an agentic workflow that reasons from measurable disease phenotypes through their circuit and cellular substrates to molecular interventions, therapeutic feasibility and clinical constraints. Finally, we introduce a human-governed in vivo lab-in-the-loop linking hypothesis generation to experimental iteration. Within this framework an agent nominated ATP1A3, the neuronal alpha3 Na+/K+-ATPase, as a control point on cortical excitability; interneuron-restricted expression of ATP1A3 abolished the beta- and gamma-band response to a focal 4-aminopyridine challenge in vivo, and the validated target was then carried into a structure-guided small-molecule campaign terminating in a defined assay to resolve the direction of modulation. CircuitATLAS thus provides a framework for discovering therapeutics based not only on what is molecularly disrupted in disease, but on what can be controlled to restore circuit function.
发表机构
- Exin Therapeutics, Inc.（埃克辛治疗公司）
机构由 AI 辅助整理，请以论文原文为准。
