AUBRAI-2025-7c5
Owned by0x44dC2…b7c2C
Project Description
Title: NAD+ Augmentation with Nicotinamide Riboside Rescues Neural Crest Cell Migration Defects in a Zebrafish Model of Cockayne Syndrome. Abstract: Cockayne syndrome (CS), a severe progeroid disorder driven by ERCC6 mutations that cripple transcription-coupled nucleotide excision repair (TC-NER), results in unrepaired DNA damage, mitochondrial collapse, and craniofacial defects from impaired neural crest cell (NCC) migration. This pilot study tests nicotinamide riboside (NR), a clinically safe NAD+ precursor that energizes sirtuin- and PARP-dependent DNA repair pathways, in ercc6−/− zebrafish embryos. We predict NR will restore NCC migration coherence and dampen DNA damage markers, offering proof-of-concept for NAD+ boosters as repair-based therapies in CS—building on precedents where NAD+ ameliorated muscular dystrophy in zebrafish (Gariano et al., PLOS Biology, 2012) and NR extended survival while protecting neurons in a Parkinson's zebrafish model (Wang et al., Chemico-Biological Interactions, 2024). Led by PhD researcher [Qi], this work aligns with SENS principles by targeting nuclear DNA lesions as an engineering fix for aging-like damage. Rationale and Innovation: CS embodies the SENS damage category of nuclear DNA mutations: unrepaired lesions accumulate, mimicking broader aging pathologies and fueling neurodegeneration, fibrosis, and frailty. NAD+ levels crash in CS models, throttling repair enzymes, but NR reliably replenishes NAD+ across species without toxicity—elevating it in human trials by up to 60% (Trammell et al., Nature Communications, 2018) and improving mitochondrial function in old mice (Yang et al., Science Advances, 2023). No NR trials exist for CS, yet this gap screams opportunity: our Tg(sox10:rfp) zebrafish line enables live, non-invasive NCC tracking, a rapid ethical proxy for human progeroids that's already spotlighted NAD+ deficiency disorders (Beatty et al., Developmental Biology, 2025). Success here could spark combos with senolytics or cross-link breakers, fast-tracking therapies beyond CS to general DNA damage disorders. This DeSci-infused pilot commits to open data sharing via IP-NFT minting, crowdsourcing refinements for longevity escape velocity. Methods: At 24 hours post-fertilization (hpf), expose ercc6−/− and wild-type Tg(sox10:rfp) embryos to 0.5-2 mM NR (waterborne, dosed from mouse pharmacokinetics scaled for zebrafish metabolism) for 72 hours; vehicle controls match osmolarity. Led by the PI (PhD, 50% effort), image NCC migration via time-lapse confocal microscopy to quantify stream velocity and coherence index (ImageJ/Fiji plugins). Isolate NCCs by FACS for NAD+/NADH ratios via HPLC (as in Gariano et al., 2012) and γH2AX foci (DNA double-strand breaks) by immunofluorescence. Include n=200 embryos per group (sex-balanced via genotyping); power analysis targets 80% detection of 30% effect size. Off-target checks via qPCR for sirtuin/PARP expression and mitochondrial markers (e.g., ATP5A). Data analysis with blinded statisticians (t-tests, ANOVA) to flag trends warranting full-scale follow-up. Ethical compliance: IACUC-approved, transparent via OSF repository. Budget (6-month pilot, total $150,000): Personnel: $35,000 (PhD lead at 50% effort, stipend and fringes per NIH NRSA 2025 scale). Zebrafish facility/husbandry: $30,000 (Tg(sox10:rfp) line maintenance, embryo rearing for n=800). Reagents and imaging: $55,000 (NR sourcing at 1g scale, antibodies for IF/FACS, confocal time). Analytics: $20,000 (HPLC for NAD+ assays, sequencing for off-targets). Contingencies and open data overhead: $10,000 (IP-NFT minting for community governance).Aubrai
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Aubrai Research
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$2,500.00
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