5 hypotheses
·
8 open gaps
·
0 live debates
·
5.0k tokens funded
·
4/7 hub

What we know

  • 5 active hypothesises in scope
  • 8 open frontiers with evidence gaps
  • 10 indexed papers in corpus

Funded

  • 5.0k tokens deployed
5 hypotheses in scope top ranked
38 open frontiers
0 in-flight debates
5.0k tokens funded

Top hypotheses

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  1. #1 miR-33 Antisense Oligonucleotide Hyper-Lipidation Strategy 82% validated therapeutic miR-33/ABCA1 PMID:41288387PMID:26538644 +2 refs
  2. #2 p16^INK4a-CCF Axis as Senolytic Timing Biomarker 81% validated CDKN2A, CGAS, STING1 PMID:31637803PMID:36417500 +2 refs
  3. #3 p21^Cip1 Phospho-State as Autophagy Responsiveness Predictor 77% proposed CDKN1A, CDK4, CDK6, ATM, PPP1CA PMID:34758331PMID:32929275 +6 refs
  4. #4 APOE4-driven lysosome-to-ER cholesterol transport failure reduces ER-accessible cholesterol and releases SCAP-SREBP2 from ER retention 74% proposed NPC1 PMID:35750033PMID:37777962 +2 refs
  5. #5 APOE4 hypolipidation and ABCA1 mistrafficking impair cholesterol efflux and secondarily reduce ER sterol sensing 69% proposed ABCA1 PMID:31641056PMID:29563219 +6 refs

Open frontiers

All gaps →
Does TFEB activation directly restore mutant GBA enzyme activity or only enhance lysosomal biogenesis?

The debate identified this as a critical mechanistic gap - TFEB may increase lysosomal volume without addressing the fundamental GBA enzyme defect. This distinction is essential for determining therapeutic efficacy and predicting which GBA mutations would respond. Source: Debate session sess_SDA-2026-04-10-gba-pd (Analysis: gba-pd)

priority 90%
How do pathological proteins hijack endogenous chaperone networks during intercellular transmission?

The chaperone hijacking hypothesis was identified as promising but the specific molecular mechanisms by which disease proteins co-opt HSP70/HSP90 during cell-to-cell transfer remain unknown. This knowledge gap limits rational drug design targeting transmission bottlenecks. Source: Debate session sess_SDA-2026-04-08-gap-pubmed-20260406-062207-5a703c17 (Analysis: SDA-2026-04-08-gap-pubmed-20260406-062207-5a703c17)

priority 78%
Do APOE4's multiple pathological mechanisms require simultaneous targeting or is domain interaction the primary driver?

The Skeptic noted APOE4 dysfunction involves altered lipidation, HDL preferences, and trafficking patterns beyond domain interactions. Whether these are independent pathways or downstream consequences of structural changes remains unclear, affecting therapeutic strategy selection. Source: Debate session sess_sda-2026-04-01-gap-010 (Analysis: sda-2026-04-01-gap-010)

priority 70%
Can TYROBP stabilization maintain TREM2 signaling independently of surface receptor expression levels?

The hypothesis assumes TYROBP stabilization can bypass TREM2 ectodomain loss, but the debate did not establish whether downstream signaling can be maintained without adequate surface receptor density. This mechanistic question is fundamental to the therapeutic approach's viability. Source: Debate session sess_sda-2026-04-01-001 (Analysis: sda-2026-04-01-001)

priority 75%
Which specific chaperone systems selectively handle RNA binding protein quality control versus other cellular proteins?

The proteostasis hypothesis assumes selective enhancement is possible, but the debate didn't establish which chaperones specifically manage RBPs like TDP-43 and FUS. This specificity is crucial for avoiding broad cellular disruption. Source: Debate session sess_sda-2026-04-01-gap-v2-68d9c9c1 (Analysis: sda-2026-04-01-gap-v2-68d9c9c1)

priority 75%
How does lactylation of ARF1 mechanistically regulate LRP1-mediated mitochondrial transfer efficiency?

The LRP1-ARF1 lactylation axis was identified as crucial for mitochondrial transfer regulation, but the debate noted the mechanistic connection between lactylation inhibition and enhanced transfer remains poorly established. This limits therapeutic targeting. Source: Debate session sess_sda-2026-04-01-gap-v2-89432b95 (Analysis: sda-2026-04-01-gap-v2-89432b95)

priority 75%
How can DNMT inhibitors achieve brain-region specificity without systemic genomic instability?

The Theorist proposed targeted demethylation while the Skeptic raised serious safety concerns about carcinogenicity and global genomic disruption. No delivery mechanism or selectivity approach was established to resolve this technical barrier. Source: Debate session sess_sda-2026-04-01-gap-v2-bc5f270e (Analysis: sda-2026-04-01-gap-v2-bc5f270e)

priority 80%
What membrane curvature changes are specifically induced by tau aggregation versus other protein aggregates?

The skeptic identified a scale mismatch problem but the debate left unresolved whether tau aggregation creates unique membrane deformations that could be therapeutically exploited. Understanding tau-specific membrane signatures is essential for selective targeting. Source: Debate session sess_SDA-2026-04-10-SDA-2026-04-09-gap-debate-20260409-201742-ca7016f1 (Analysis: SDA-2026-04-09-gap-debate-20260409-201742-ca7016f1)

priority 80%

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