Connective Tissue Research Proposals
1 Study C-1: HIF-1alpha-ECM Dynamics in ME/CFS
Longitudinal study measuring HIF-1alpha, MMP-3, MMP-9, and collagen degradation markers (CTX, NTx) at rest, immediately post-exertion, and 24/48/72h post-CPET in ME/CFS vs controls. Hypothesis: ME/CFS will show delayed HIF-1alpha elevation and prolonged MMP elevation correlating with PEM timing.
2 Study C-2: Connective Tissue Stratification by Upright MRI
Cross-sectional (n=200 ME/CFS) with upright MRI to assess CCI prevalence in unselected cohort. Stratify by Beighton score and orthostatic symptoms. Hypothesis: CCI prevalence lower than Bragee2020 (80%) but higher than general population, with association to hypermobility and orthostatic symptoms.
3 Study C-3: Mast Cell Stabilizer + Low-Dose Doxycycline Trial
RCT (n=80, 4 arms: placebo, mast cell stabilizer alone, doxycycline alone, combination). Outcome: mast cell markers, MMP levels, connective tissue symptoms. Hypothesis: combination therapy shows synergistic benefit.
4 Study C-4: Circadian Collagen Synthesis Optimization
Pilot testing timed vitamin C and proline supplementation (circadian-appropriate dosing) vs uncontrolled supplementation in hypermobile ME/CFS. Measure collagen synthesis markers (PINP, PIIINP) at multiple timepoints.
5 Study D-1: DecodeME Stratified GWAS by Onset Age
Background. The DecodeME dataset contains genetic data for over 17,000 ME/CFS participants, but no GWAS has yet stratified by age at onset. The vitiligo precedent demonstrates that bimodal-onset analysis can reveal fundamentally distinct genetic architectures: early-onset vitiligo harbours an MHC class II haplotype with OR > 8 that is entirely absent from late-onset disease (Jin et al. 2019). ME/CFS shows clinically meaningful differences between early and late onset: greater severity (OR 2.15), more infectious mononucleosis triggers (OR 2.32), and increased familial clustering (OR 1.43) in the early peak (McGrath et al. 2026).