Microglial metabolic reprogramming to alleviate retinal degeneration

• Applicant: Dr. Thomas Winogrodzki
• Subject Area: Ophthalmology ; Immunology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 565593203

Retinitis pigmentosa (RP), is a leading cause of progressive vision loss with limited therapeutic options. While gene therapies show promise, current approaches are limited to certain mutations, exclude patients with complex or unidentified genetic causes and frequently induce inflammation. Thus, generalizable treatments addressing shared disease mechanisms are urgently needed. This proposal hypothesizes that microglial metabolic reprogramming via constitutive Pgc1α overexpression can alleviate retinal degeneration by reducing disease-associated neuroinflammation in a translationally more relevant mouse model of RP. WP1 assesses the impact of Pgc1α overexpression on retinal structure, function, and inflammation, providing in vivo insights into its therapeutic potential. Using a novel primary retinal culture method, WP2 investigates differences in the immunometabolic profile of Pgc1α-overexpressing and control retinal microglia, employing real-time metabolic flux analyses, stable isotope tracing, and cytokine quantification. This research is among the first to introduce mutation-independent microglial metabolic reprogramming as a strategy to slow retinal degeneration and reduce inflammation. Unlike current therapies, it addresses shared mechanisms across inherited and age-related retinal disorders. Preliminary data indicate that microglia-specific constitutive Pgc1α overexpression reduces glycolytic dependency by increasing mitochondrial function, and promotes non-inflammatory phenotypes in primary retinal microglia, while improving photoreceptor survival in a preclinical model of RP. By advancing these findings, this project will establish microglia-specific metabolic reprogramming as a novel, broadly applicable therapeutic option for ocular and neurodegenerative diseases. My goal is to address significant societal challenges by developing therapies to prevent blindness, with a focus on RP as its prevalence rises in an aging population. This fellowship will strengthen my expertise in gene therapy and metabolic reprogramming within a translational research environment. Under the mentorship of Prof. Tsang, I will gain critical feedback, acquire advanced skills in vision research, and benefit from Columbia's career workshops and professional networks. These experiences will prepare me to transition into an independent investigator role, advancing next-generation therapies for retinal and neurodegenerative diseases.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Stephen H. Tsang, Ph.D.