Sunday, May 18, 2025
5/18/2025
Smad4 is a master regulator for extracellular matrix homeostasis in the corneal stroma - PROJECT SUMMARY/ABSTRACT___________________________________________________________ Transforming growth factor-beta (TGF-β) is one of the most important growth factors involved in morphogenesis of ocular anterior segment tissues including corneal stroma, a transparent tissue layer responsible for acquiring normal vision. To elucidate the role of TGF-β signaling pathway in the corneal stroma, we discovered that TGF- β receptor 1 (Tbr1) and Smad4 knockout (KO) mice showed bilateral corneal stroma thinning phenotype, but the phenotypic manifestations between them were distinct. Smad4 KO exhibited nonprogressive and uniform corneal thinning from limbus to limbus; however, Tbr1 KO mice displayed progressive and irregular/uneven corneal thinning. Interestingly, the more severe corneal thinning in Tbr1 KO mice can be rescued by simultaneously deleting the Smad4 in Tbr1/Smad4 double knockout (DKO) mice. In other words, the phenotypic manifestation of the Tbr1/Smad4 DKO recapitulated Smad4 KO but not the Tbr1 KO phenotype. Because corneal stromal morphogenesis and homeostasis rely on the balance between ECM synthesis and degradation, we hypothesize that Smad4 not only plays a pivotal role in the Tbr1-dependent ECM synthesis pathway but also participates in the Alk1/Smad1,5-dependent ECM degradation pathway. This makes the Smad4 a key regulator that controls ECM synthesis and ECM degradation in the corneal stroma. We propose the following Specific Aims to establish an equivalent role of Smad4 in Tbr1-independent and Alk1/Smad1,5-dependent ECM degradation pathway which is critical for corneal stromal morphogenesis and homeostasis. Specific Aim 1: . Rescue of the progressively stromal thinning phenotype of Tbr1 KO by targeting components of Alk1/Smad1,5/Smad4 axis through gene knockout or chemical inhibitors. Specific Aim 2: To determine that Smad1, Smad5, and Smad4 have similar chromosome binding profiles in Tbr1 KO keratocytes through genome-wide chromatin immunoprecipitation (ChIP) assays with next- generation sequencing (NGS). Impact: Completion of these proposed aims in two years will provide new knowledge regarding the critical roles of Smad4 as a key regulator that controls both ECM synthesis and degradation for the corneal stromal morphogenesis and maintenance of tissue homeostasis-serving as the basis for the long-term goal of improving eye care and related ocular diseases like corneal ectasia.
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