The parent grant (R01 EY027785; funding period 2/1/2018 - 1/31-2023) is titled “Prevention of Macular Pathophysiology Associated with F3 Misfolding”. Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in people greater than 60 years of age in industrialized countries. Worldwide, it is estimated that nearly 300 million people will have some form of AMD by 2040. Thus far, no effective treatment exists for halting dry AMD progression, the form which affects 90% of all AMD patients. The only suggestion for slowing this form of the disease is to take high-dose vitamin and mineral supplements daily. Emerging evidence suggests that mutations or alterations in fibulin-3 (F3), a secreted protein of unknown function, plays a prominent role in influencing the pathogenesis of macular degenerative diseases. One specific example is how an R345W mutation in F3 causes an early onset macular dystrophy called Malattia Leventinese (ML), which is characterized by complement activation and production of inflammatory cytokines, as well as sub-retinal pigment epithelium (RPE) deposits. Furthermore, a D49A mutation in F3 has been associated with development of AMD in patients with cuticular drusen. In general however, there is a lack of knowledge regarding how these macular degenerations develop and how they might be influenced by F3. Furthermore, there are no effective treatments for either ML or the more prevalent disease, dry AMD. Therefore, there is an urgent need to develop a mechanistic understanding of the underlying causes of AMD-like diseases, such as ML, and to identify new therapies for them. The research proposed in this parent grant will; i) test strategies directed at preventing the secretion of misfolded F3 from cells and evaluate the consequences thereof, ii) employ a novel, conditional approach to regulate inflammatory signaling downstream of F3 misfolding, and iii) test whether WT F3 is necessary for sub-RPE deposit formation. Ultimately, at completion of these studies, we hope to have a better understanding of the molecular basis by which misfolded F3 facilitates inflammation and sub-RPE protein deposition, and to identify a number of therapeutically-tractable approaches for treating ML. The insight that we gain regarding how misfolded F3 is involved in triggering inflammation and sub-RPE deposits can likely be applied more broadly to prevalent retinal diseases such as dry AMD. Aim 1 of the grant addresses the idea that therapeutically directed regulation of F3 folding and/or secretion may serve as a way to treat the underlying cause of ML and other diseases caused by F3 misfolding. DaNae will be focused on making contributions towards developing a deeper understanding of how mutations in F3 lead to ocular disease, such as AMD and ML, and manipulating cellular quality control mechanisms to prevent F3- associated disease.