ID: h-241752cd
Hypothesis
CD38 Inhibition for NAD+ Restoration and Microglial Senescence Prevention
High risk.
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 4 support✗ 4 oppose
✓ All Quality Gates Passed
🧪 Overview
High risk. The Expert identifies a fatal flaw: CD38 is predominantly expressed in peripheral immune cells (B cells, T cells, NK cells), not microglia. The cited 3-4 fold increase in PD substantia nigra microglia may reflect perivascular macrophage infiltration rather than intrinsic microglial CD38. Multiple clinical-stage CD38 inhibitors exist (evobrutinib approved for MS), but none are being developed for neurodegeneration. This hypothesis should not proceed without microglial-specific CD38 validation in human PD substantia nigra using single-cell approaches.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["Target Gene: CD38"]
B["Molecular Mechanism<br/>Pathway Activation"]
C["Cellular Phenotype<br/>Neuronal or Glial Response"]
D["Network Effect<br/>Circuit-Level Consequence"]
E["Disease Relevance<br/>Neurodegeneration Link"]
A --> B --> C --> D --> E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#1b5e20,stroke:#81c784,color:#81c784⚖️ Evidence
⚖️ Evidence Matrix4 supports4 contradicts
Supports
Multiple CD38 inhibitors clinically available (evobrutinib approved for MS)
Contradicts
CD38 is predominantly expressed in peripheral immune cells, not microglia
Contradicts
CD38 in neurons functions primarily in calcium signaling, not NAD+ metabolism
Contradicts
Direct NAD+ precursor supplementation shows inconsistent CNS effects in human trials
Contradicts
Species differences: murine microglia express CD38 at much lower basal levels
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — CD38
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for CD38 from GTEx v10.
💉 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.
No DepMap CRISPR Chronos data found for CD38.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we perform single-cell RNA sequencing (scRNA-seq) of CD45+ immune cells isolated from post-mortem Parkinson's disease substantia nigra tissue AND stratify cells by canonical microglial markers (P2R | CD38 expression (log2 normalized counts) will be significantly elevated (p<0.001) in P2RY12-negative perivascular macrophages relative to P2RY12-positive microg | — no observation — | pending | 0.65 |
| IF we administer a CNS-penetrant CD38 inhibitor (evobrutinib at 20mg/kg twice daily, blood-brain barrier penetrating formulation) to C57BL/6 mice for 4 weeks following MPTP-induced dopaminergic lesion | CD38 inhibitor treatment will show ≤10% change in p21+/Iba1+ microglial density (expected ~15 cells/field in vehicle) and ≤5% change in TH+ neuron count (expect | — no observation — | pending | 0.45 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF we perform single-cell RNA sequencing (scRNA-seq) of CD45+ immune cells isolated from post-mortem Parkinson's disease substantia nigra tissue AND stratify cells by canonical microglial markers (P2RY12+, TMEM119+, CD64+) versus perivascular macrophage markers (P2RY12-, CD206+, LYVE1+) versus perip
Predicted outcome: CD38 expression (log2 normalized counts) will be significantly elevated (p<0.001) in P2RY12-negative perivascular macrophages relative to P2RY12-posit
Falsification: If scRNA-seq reveals CD38 expression in microglia (P2RY12+/TMEM119+/CD64+ cells) that is comparable to or exceeds expression in perivascular macrophages (fold-change <1.5), the hypothesis that CD38 is
pendingconf 45%
IF we administer a CNS-penetrant CD38 inhibitor (evobrutinib at 20mg/kg twice daily, blood-brain barrier penetrating formulation) to C57BL/6 mice for 4 weeks following MPTP-induced dopaminergic lesion AND compare outcomes to vehicle-treated controls, THEN we will observe no significant difference in
Predicted outcome: CD38 inhibitor treatment will show ≤10% change in p21+/Iba1+ microglial density (expected ~15 cells/field in vehicle) and ≤5% change in TH+ neuron cou
Falsification: If CD38 inhibitor treatment produces ≥30% reduction in microglial p21+/Iba1+ cell density AND/OR ≥25% increase in TH+ neuron survival compared to vehicle controls, the hypothesis that peripheral CD38
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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