Diabetic Retinopathy

Goal: Study the role of CD40-TRAF signaling in promoting various events critical to de development of diabetic retinopathy.

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Background

Diabetic retinopathy is the leading cause of blindness in working age adults in US. We demonstrated that CD40 is a central mediator of inflammatory responses in the diabetic retina and is required for development of diabetic retinopathy. 

Figure 1

Portillo, J. C., Yu, J. S., Vos, S., Bapputty, R., Lopez Corcino, Y., Hubal, A., Daw, J., Arora, S., Sun, W., Lu, Z. R., & Subauste, C. S. (2022). Disruption of retinal inflammation and the development of diabetic retinopathy in mice by a CD40-derived peptide or mutation of CD40 in Müller cells. Diabetologia, 65(12), 2157–2171. https://doi.org/10.1007/s00125-022-05775-6 

Using transgenic Cd40-/- mice with selective rescue of CD40 in retinal Muller cells, we uncovered a CD40 → ATP → P2X7 pathway that drives inflammatory responses in the diabetic retina (Figure 1). Using transgenic mice generated in the lab, we also showed that disruption of CD40-TRAF2,3 signaling ablates retinal inflammation and prevents the development of diabetic retinopathy. We developed and patented a cell-permeable CD40-TRAF2,3 blocking peptide as a pharmacologic approach to block CD40-TRAF2,3 signaling. This peptide has retro-inverso features making it resistant to degradation by peptidases. We reported that intravitreal administration of the CD40-TRAF2,3 peptide to diabetic mice ablates the inflammatory responses key for development of diabetic retinopathy. We are currently using transgenic mice to examine the role of CD40 in various other processes that are key to the development of diabetic retinopathy.