Role of Interphotoreceptor Matrix Proteoglycans in Retinal Homeostasis and Retinitis Pigmentosa - Abstract: The extracellular matrix (ECM) plays a pivotal role in the structural integrity and biochemical functioning of neuronal tissues. Within the retina, a specific ECM known as the interphotoreceptor matrix (IPM) interfaces photoreceptors with the retinal pigment epithelium (RPE), implying a significant role in key processes such as nutrient transport, the visual cycle, and phagocytosis of outer segments. Mutations affecting the IPM lead to blinding diseases; however, the specific role of the IPM in retina homeostasis and blinding diseases remains elusive. This project explores the function of two functionally interdependent proteoglycans, IMPG1 and IMPG2, within the IPM and how mutations in these molecules are associated with retinitis pigmentosa (RP). Specifically, we propose three comprehensive aims: AIM 1. Investigate IMPG1/2 role in the retina-RPE nutrient exchange. Using an IMPG1/2-double knockout mouse model, this aim will test how IMPG1/2 facilitates the nutrient interchange between the retina and RPE and its link to adult-onset RP. Fluorescent and 13C6-glucose probes will be used to assess the nutrient flux between RPE and photoreceptors. AIM 2. Determine the mechanisms that lead to childhood-onset RP linked to IMPG2 mutations. Employing newly developed mouse models based on human disease, the study will elucidate the role of truncated IMPG2 proteins in accelerating the onset of RP and test gene therapy strategies. AIM 3. Identify the cause of RP linked to IMPG1 mutations. This aim proposes that mutations affecting the standard proteolysis of IMPG1 lead to intracellular protein accumulation and rod degeneration. A new mouse model, IMPG1-L583P, will be employed to test this hypothesis and treatment strategies. This research project seeks to delineate the role of IPM in retina homeostasis and unravel the mechanisms of RP disease linked to IMPG1 and IMPG2 mutations. Furthermore, this project uses new mouse models based on human diseases to test therapeutic approaches. Understanding the role of ECMs on the neuron-glia interaction holds significant potential to comprehend a broad spectrum of neuronal and retinal diseases and identify novel therapeutic avenues.
