🧪
hypothesis

Dual SPI1 Inhibition for Atherosclerosis-Neurodegeneration Axis

Hypothesis

Dual SPI1 Inhibition for Atherosclerosis-Neurodegeneration Axis

Since SPI1 regulates inflammatory responses in both peripheral atherosclerosis and central neuroinflammation, a brain-penetrant SPI1 modulator could simultaneously target vascular disease and prevent secondary neurodegeneration.
🧬 SPI1🩺 neuroinflammation🎯 Composite 46%💱 $0.52▲5.8%active
EvidencePending (0%)📖 5 cit🗣 1 debates 5 support 3 oppose
✓ All Quality Gates Passed
Mechanistic 0.50 (15%) Evidence 0.50 (15%) Novelty 0.50 (12%) Feasibility 0.50 (12%) Impact 0.00 (12%) Druggability 0.50 (10%) Safety 0.50 (8%) Competition 0.50 (6%) Data Avail. 0.50 (5%) Reproducible 0.50 (5%) KG Connect 0.50 (8%) 0.455 composite
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arXiv PreprintNeurIPSNature MethodsPLOS ONE
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Composite46%

🧪 Overview

Since SPI1 regulates inflammatory responses in both peripheral atherosclerosis and central neuroinflammation, a brain-penetrant SPI1 modulator could simultaneously target vascular disease and prevent secondary neurodegeneration. This represents a novel vascular-neural protection therapeutic strategy.

🧬 Mechanism

🔗 Mechanism from KG for SPI1

Auto-built from this analysis's top knowledge-graph edges.

graph TD
    SPI1["SPI1"] -->|encodes| PU_1["PU.1"]
    SPI1_1["SPI1"] -->|regulates| C1Q["C1Q"]
    SPI1_2["SPI1"] -->|contributes to| neuroinflammation["neuroinflammation"]
    SPI1_3["SPI1"] -->|regulates| glycolytic_metabolism["glycolytic_metabolism"]
    SPI1_4["SPI1"] -->|regulates| microglia["microglia"]
    C1Q_5["C1Q"] -->|enhances| SPI1_6["SPI1"]
    SPI1_7["SPI1"] -->|causes| neuroinflammatory_memory["neuroinflammatory_memory"]
    SPI1_8["SPI1"] -.->|inhibits| synaptic_plasticity["synaptic_plasticity"]
    SPI1_9["SPI1"] -->|orchestrates| neurovascular_unit["neurovascular_unit"]
    SPI1_10["SPI1"] -->|amplifies| neuroinflammation_11["neuroinflammation"]
    SPI1_12["SPI1"] -->|modulates| chromatin_accessibility["chromatin_accessibility"]
    chronic_vascular_inflamma["chronic_vascular_inflammation"] -->|regulates| SPI1_13["SPI1"]
    SPI1_14["SPI1"] -->|maintains| microglial_activation["microglial_activation"]
    SPI1_15["SPI1"] -->|associated with| atherosclerosis["atherosclerosis"]
    SPI1_16["SPI1"] -->|regulates| Inflammatory_gene_express["Inflammatory gene expression"]
    style SPI1 fill:#ce93d8,stroke:#333,color:#000
    style PU_1 fill:#4fc3f7,stroke:#333,color:#000
    style SPI1_1 fill:#ce93d8,stroke:#333,color:#000
    style C1Q fill:#ce93d8,stroke:#333,color:#000
    style SPI1_2 fill:#ce93d8,stroke:#333,color:#000
    style neuroinflammation fill:#4fc3f7,stroke:#333,color:#000
    style SPI1_3 fill:#ce93d8,stroke:#333,color:#000
    style glycolytic_metabolism fill:#81c784,stroke:#333,color:#000
    style SPI1_4 fill:#ce93d8,stroke:#333,color:#000
    style microglia fill:#4fc3f7,stroke:#333,color:#000
    style C1Q_5 fill:#ce93d8,stroke:#333,color:#000
    style SPI1_6 fill:#ce93d8,stroke:#333,color:#000
    style SPI1_7 fill:#ce93d8,stroke:#333,color:#000
    style neuroinflammatory_memory fill:#4fc3f7,stroke:#333,color:#000
    style SPI1_8 fill:#ce93d8,stroke:#333,color:#000
    style synaptic_plasticity fill:#4fc3f7,stroke:#333,color:#000
    style SPI1_9 fill:#ce93d8,stroke:#333,color:#000
    style neurovascular_unit fill:#4fc3f7,stroke:#333,color:#000
    style SPI1_10 fill:#ce93d8,stroke:#333,color:#000
    style neuroinflammation_11 fill:#4fc3f7,stroke:#333,color:#000
    style SPI1_12 fill:#ce93d8,stroke:#333,color:#000
    style chromatin_accessibility fill:#4fc3f7,stroke:#333,color:#000
    style chronic_vascular_inflamma fill:#4fc3f7,stroke:#333,color:#000
    style SPI1_13 fill:#ce93d8,stroke:#333,color:#000
    style SPI1_14 fill:#ce93d8,stroke:#333,color:#000
    style microglial_activation fill:#4fc3f7,stroke:#333,color:#000
    style SPI1_15 fill:#ce93d8,stroke:#333,color:#000
    style atherosclerosis fill:#ef5350,stroke:#333,color:#000
    style SPI1_16 fill:#ce93d8,stroke:#333,color:#000
    style Inflammatory_gene_express fill:#4fc3f7,stroke:#333,color:#000

⚖️ Evidence

⚖️ Evidence Matrix5 supports3 contradicts
Supports
Adult-onset CNS myelin sulfatide deficiency is sufficient to cause Alzheimer's disease-like neuroinflammation and cognitive impairment.
Mol Neurodegener2021PMID:34526055medium
Supports
A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation.
J Exp Med2023PMID:37642942medium
Supports
Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology.
Nat Commun2022PMID:35013236medium
Supports
SPI1 triggers the formation of neutrophil extracellular traps in multiple sclerosis through CXCL4.
J Mol Histol2025PMID:40632337medium
Supports
Revealing the nervous system requirements of Alzheimer disease risk genes in Drosophila.
Am J Hum Genet2025PMID:41167194medium
Contradicts
Microglial phagocytosis in Alzheimer disease.
Nat Rev Neurol2026PMID:41315858medium
Contradicts
Alzheimer's Disease Genetics: A Dampened Microglial Response?
Neuroscientist2023PMID:34142603medium
Contradicts
Late onset Alzheimer's disease genetics implicates microglial pathways in disease risk.
Mol Neurodegener2017PMID:28549481medium
📖 Linked Papers

No linked papers recorded for this hypothesis yet.

🏥 Translation

🧬 3D Protein Structure — SPI1

No curated PDB or AlphaFold mapping for SPI1 yet. Search RCSB →

💉 Clinical Trials

No clinical trials data linked to this hypothesis yet.

No curated ClinVar variants loaded for this hypothesis.

Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.

🔍 Search ClinVar for SPI1 →

No DepMap CRISPR Chronos data found for SPI1.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

🏆 Tournament

🏆 Arenas / Elo

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📊 Market Indicators

7d Trend
Stable
7d Momentum
▲ 0.0%
Volatility
High
0.0530
Events (7d)
0
Price History
▲5.8%

💾 Resource Usage

LLM Tokens
10,898
$0.0654
Total Cost
$0.0654
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