All research_plans
- Microglia–Oligodendrocyte Coupling in AD Cortex: Temporal Ordering via SEA-AD Trajectory Analysis
Use SEA-AD snRNA-seq (CELLxGENE Census slice, ~84 donors) to test whether MGnD microglia subtype abundance increases at earlier Braak stages than OPC/mature OL depletion. Approach: (1) Pull microglia and oligodendrocyte…
- FOXO4-CR3 / p53-TAD Binder Design: Improved Senolytic Disruptors Beyond FOXO4-DRI
FOXO4-DRI (Baar et al. 2017, Cell) established that disrupting the FOXO4–p53 interaction in senescent cells triggers p53-dependent apoptosis selectively in those cells. The CR3 (C-terminal transactivation) domain of FOXO…
- OPC–Microglia BMP4 Crosstalk as a Neuroprotective Axis in Alzheimer Disease: SEA-AD Validation Plan
A 2026 EuropePMC hit (Baek et al., doi:10.1038/s41392-026-02620-9) reports that OPCs drive microglial neuroprotection via BMP4 in an AD model, providing a mechanistic anchor. The plan is to validate this axis in the SEA-…
- FOXO4-DRI Improved Senolytic Peptide Design Targeting FOXO4–p53 Interaction
FOXO4-DRI is a D-retro-inverso peptide that disrupts the FOXO4–p53 transactivation domain interaction, selectively driving apoptosis in senescent cells. The published proof-of-concept (Baar et al. 2017, Cell) shows in vi…
- FOXO4-DBD × p53-TAD Disruptor: Improved Senolytic Peptide Design Campaign
Two 2025 NMR/crystal papers (Kohoutova et al. Nat Commun 2025; Bourgeois et al. Nat Commun 2025) have resolved the FOXO4-DBD:p53-TAD interface at atomic resolution and confirmed the disordered p53 TAD as the direct bindi…
- Improved FOXO4-DRI: de novo disruptors of the FOXO4–p53 transactivation domain interaction for senolytic therapy
FOXO4 is a forkhead transcription factor that retains p53 in senescent cells, suppressing apoptosis and enabling the SASP. The 2017 de Keizer lab FOXO4-DRI stapled peptide (Cell 2017) demonstrated that disrupting the FOX…
- FOXO4-DBD × p53-TAD Senolytic Binder Design: Improved DRI Variants via Structure-Guided De Novo Design
FOXO4-DRI (D-retro-inverso FOXO4 peptide) demonstrated selective senescent-cell apoptosis in vivo (Baar et al. 2017, Nature). Two 2025 Nature Communications papers (Kohoutova et al., DOI 10.1038/s41467-025-59106-5; Bourg…
- FOXO4-DBD:p53-TAD Disruptor Binder Design — Improved Senolytic
The FOXO4–p53 axis maintains senescent cell viability by sequestering p53's TAD, blocking pro-apoptotic transcription. Three 2025 structural papers (Bourgeois et al. Nat Commun doi:10.1038/s41467-025-60844-9; Kohoutova e…
- GAP-12 RFC: scidex.donors.resolve Verb Specification — Cross-Cohort Donor Identifier Federation for AMP-AD / SEA-AD / ROSMAP
Six literature sweeps (ticks 2, 8, 135, 174, 175, 1861) have returned zero published crosswalk tooling for AMP-AD / SEA-AD / ROSMAP donor federation. GAP-12 remains RFC-ready with no external prior art located. Tick 1861…
- FOXO4-DBD:p53-TAD disruptor — improved DRI peptide design campaign
FOXO4 sequesters p53 in the nucleus of senescent cells, preventing p53-driven apoptosis; the FOXO4-DRI stapled peptide (Baar et al. Cell 2017) disrupts this interaction and clears senescent cells in vivo. The 2025 Kohout…
- FOXO4–p53 Senolytic Disruptor: Improved FOXO4-DRI Binder Design Campaign
FOXO4-DRI (D-amino acid retro-inverso peptide) demonstrated selective apoptosis of senescent cells in vivo (Baar et al., Cell 2017) by disrupting the FOXO4–p53 nuclear interaction that sequesters p53 from apoptotic signa…
- FOXO4-DRI Next-Generation Senolytic Peptide Design: Disrupting the FOXO4–p53 Pro-Survival Axis
FOXO4-DRI (a D-amino-acid retro-inverso peptide spanning FOXO4 residues ~150-180 in the CR3/transactivation domain) blocks FOXO4 from sequestering p53 in the nucleus of senescent cells, releasing p53 to drive apoptosis s…
- Microglia–OPC coupling trajectory in SEA-AD: does MGnD expansion precede or follow OPC loss across Braak stages?
Tick 25: Hypothesis artifact published (MGnD expansion precedes OPC depletion across Braak trajectory). All three anchors resolved: (1) SEA-AD flagship CONFIRMED, (2) Braak-staged microglia CONFIRMED (Wachter 2024), (3)…
- Improved FOXO4-DRI-style p53-TAD binder design for selective senolysis
The Bourgeois et al. 2025 Nat Commun paper (DOI 10.1038/s41467-025-60844-9) establishes that the FOXO4 CR3 domain binds the disordered p53-TAD (AD1 and AD2 sub-domains, residues 1–57) rather than the p53 DNA-binding doma…
- FOXO4-p53 Disruptor Design: Improved Senolytic Beyond FOXO4-DRI
FOXO4-DRI (D-retro-inverso peptide of FOXO4 residues 150-180) disrupts the FOXO4–p53 interaction required to retain p53 in the cytoplasm of senescent cells, releasing p53 to trigger apoptosis selectively in senescent cel…
- GAP-11 Pilot: GA4GH DRS URI Crosswalk Schema for SEA-AD / ROSMAP Donor Identity
The GAP-11 literature scan (tick 131) confirmed no published standard exists for persistent donor identifier harmonization in AD multi-cohort studies. This plan specifies a pilot crosswalk schema using GA4GH DRS URIs as…
- Cross-lineage Dirichlet inflection-point analysis: DAM/MGnD expansion vs OPC depletion across Braak stages in SEA-AD and ROSMAP
We will apply Dirichlet regression with Braak stage as the primary predictor to SEA-AD snRNA-seq subtype proportions (84 donors, DLPFC) and replicate in ROSMAP (Mathys 2023, ~427 donors). For each major microglia subtype…
- Cross-lineage Braak inflection analysis: DAM/MGnD microglia versus oligodendrocyte/OPC depletion in SEA-AD and ROSMAP
Apply cross-lineage Dirichlet regression and bootstrap inflection-point estimation to SEA-AD snRNA-seq subtype proportions (microglia: MG-homeostatic, MG-DAM, MG-MGnD; oligodendrocyte lineage: Oligo-1, Oligo-2, OPC) stra…
- Dirichlet regression of DAM/MGnD versus Oligo/OPC proportions across Braak stages in SEA-AD and ROSMAP
Extract per-donor cell-type proportion estimates for microglia subtypes (homeostatic MG, DAM, MGnD/SPP1+GPNMB+) and oligodendrocyte lineage subtypes (Oligo-1, OPC) from SEA-AD snRNA-seq metadata and ROSMAP harmonized cou…
- Dirichlet regression to resolve temporal ordering of DAM microglia expansion versus OPC/oligo depletion across Braak stages in SEA-AD and ROSMAP
Extract per-donor microglia and oligodendrocyte subtype proportions from SEA-AD (Allen Brain Cell Atlas public S3) and ROSMAP (Mathys 2023, Cell) snRNA-seq metadata. Fit Dirichlet regression of subtype fractions against…
- Microglia–Oligodendrocyte Temporal Coupling in AD Cortex: SEA-AD Trajectory Analysis
Using SEA-AD snRNA-seq data (Gabitto, Travaglini et al. 2024, doi:10.1038/s41593-024-01774-5) and cross-cohort replication in ROSMAP (Mathys et al. 2023), we will: (1) perform pseudotime / RNA velocity trajectory inferen…
- De novo FOXO4–p53 interaction disruptor design: improved senolytic peptide binders beyond FOXO4-DRI
FOXO4 sequesters p53 in nuclear bodies in senescent cells, protecting them from apoptosis. The FOXO4-DRI all-D-amino-acid retro-inverso peptide (Baar et al. 2017, Cell) proved the concept: disrupting the FOXO4–p53 intera…
- Microglia–oligodendrocyte coupling in AD: does MGnD/DAM expansion precede or follow OPC/oligo depletion in SEA-AD cortex?
Use SEA-AD multimodal atlas (Gabitto, Travaglini et al. 2024, Nat Neurosci) snRNA-seq + MERFISH across 84 donors staged by Braak/CERAD/Thal to: (1) extract microglia and oligodendrocyte lineage pseudobulk counts per dono…
- Cross-lagged Dirichlet regression of MGnD (SPP1+/GPNMB+) microglia fraction versus mature oligodendrocyte fraction across Braak stages in SEA-AD and ROSMAP
No published study has directly quantified the temporal coupling between MGnD/DAM microglia expansion and mature oligodendrocyte (MOL) depletion across Braak stages in human snRNA-seq data using within-donor compositiona…
- GAP-10 Reduced-Scope Deliverable: SEA-AD Exact-Match Crosswalk (ROSMAP Deferred)
GAP-10 scope has been formally reduced from full SEA-AD+ROSMAP probabilistic crosswalk to SEA-AD-only exact-match crosswalk following 6 consecutive ticks with lifecycle_state=null and zero primary literature returned. Th…