Heparan Sulfate Regulation of HTRA1-Mediated Proteostasis in Bruch's Membrane in Age-Related Macular Degeneration

Our goals are to determine how HTRA1 regulates Bruch’s membrane proteostasis and to understand how altered heparan sulfate expression affects HTRA1 activity in age-related macular degeneration.

Age-related macular degeneration (AMD), a leading cause of central vision loss, affects 200 million people worldwide. AMD is marked by changes in Bruch’s membrane (BrM), where drusen deposits disrupt macular function and lead to vision loss, particularly in the untreatable dry form. HTRA1, a key protein linked to AMD, interacts with heparan sulfate (HS), a molecule elevated in AMD-affected BrM. This study explores how HS impact HTRA1 function, contributing to AMD progression. Findings could guide new therapies targeting HS or enhancing HTRA1 to protect vision in AMD patients.

This proposal is innovative because it integrates isotope-labeled degradomics with glycan biology to uncover the full repertoire of HTRA1 substrates in Bruch’s membrane. By combining this with advanced biochemical assays, we uniquely explore how heparan sulfate modulates HTRA1 activity, providing mechanistic insight into drusen formation. This approach bridges genetics, proteomics, and glycobiology to reveal novel therapeutic targets for early intervention in AMD.

Completion of this study will broaden the understanding of how HTRA1 and heparan sulfate drive early AMD pathology, providing a foundation for new therapeutic targets beyond current approaches. By revealing how modulating heparan sulfate (HS) in Bruch’s membrane can influence HTRA1 activity, this work could guide the development of HS-based therapies to prevent or slow drusen formation. These insights have the potential to transform AMD management and advance the broader field of protease–glycan biology.