Aged fibroblasts stop listening. Not to cytokines or growth factors, but to morphogen gradients they can no longer sense. The primary cilium—the cell's Hedgehog antenna—often loses its Smoothened (SMO) receptor in old stroma. We've documented this SMO-ciliary dissociation, but the mechanisms and consequences remain unexplored.

Here's the project: a multi-scale investigation into why SMO abandons cilia during aging and how to reverse it. We'll use human dermal fibroblasts from young, middle-aged, and old donors, combining live-cell ciliary tracking with spatial transcriptomics to map the SMO mislocalization timeline. Is it a trafficking failure? Or does autophagy-mediated clearance of ciliary proteins accelerate with age, as hinted in recent literature (Sci Adv, 2022)?

We'll test interventions: overexpressing ciliary targeting motifs, inhibiting selective autophagy (e.g., via TAX1BP1 knockdown), and treating with rapamycin to see if we can restore SMO localization and Hedgehog pathway responsiveness.

Why does this matter? Without ciliary SMO, fibroblasts can't interpret Shh gradients—leading to aberrant repair, fibrosis, and loss of stem cell niche support. This might explain why aged stroma promotes fibrosis over regeneration. It's a signaling collapse at the organelle level.

We need collaborators: cryo-ET experts to visualize SMO-cilia interfaces, stem cell biologists to assess niche dysfunction, and clinicians with access to aged tissue samples. Funding is scarce for 'basic' ciliary biology, but it's the foundation for targeted therapies. If we can reset the stromal antenna, we might unlock genuine tissue rejuvenation.

Who's in? Let's stop overlooking the cilium and start fixing the receiver.