The extracellular matrix (ECM) is a fundamental component in cell biology. The ECM is essential for maintaining the structural and biochemical integrity of any tissue. This complex network of proteins and polysaccharides is dynamic and experiences continuous remodeling depending on various physiological and pathological stimuli.

Diagram of a neural cell with labels indicating regions, including RPE, OS, IS, and Müller cells, alongside a scale bar measuring IPM.

The interphotoreceptor matrix (IPM) is a specialized ECM that envelops the photoreceptor cells in the retina and is essential for retinal health and function. It supports structural stability, facilitates nutrient and waste exchange, and mediates crucial biochemical and biomechanical signals necessary for retinal development, immune responses, and disease progression.

Our research is dedicated to decoding the complex roles of the IPM, Its composition, and synthesis. We endeavor to elucidate how the IPM contributes to the progression of visual impairments such as diabetic retinopathy, macular degeneration, and retinitis pigmentosa. By understanding these mechanisms, we aim to innovate therapeutic approaches to overcome these conditions.

Our laboratory utilizes genetically modified mice models, high-resolution microscopy, optical coherence tomography, electrophysiology, adenovirus-mediated gene expression in mice, and various biochemical techniques to analyze protein interactions. We also employ cutting-edge tools such as proteomics, RNA sequencing, and metabolomics to explore the role of IPM in the retina.

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Understand the neuronal ECM, besides its potential to cure blinding diseases, has a broad impact on diverse scientific fields such as aging, neurodegeneration, biomaterials, brain-machine interface, 3D tissue culture, and computational neuroscience.

Areas of interest

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Synthesis and composition of the IPM

The IPM is compounded by a mesh of molecules that are constantly synthesized and degraded. We aim to identify these molecules, understand their interactions, and determine their mechanism of matrix assembly.

Our studies are centered on two important proteins conserved across species and linked to human diseases. These proteins are known as "interphotoreceptor matrix proteoglycans 1 and 2" (IMPG1 and IMPG2). They are proteoglycans rich in glycosylation and chondroitin sulfate. Rods and cones photoreceptors synthesize these proteins in the inner segments (IS). We aim to answer several questions related to these proteins such as: How do IMPG1 and IMPG2 molecules combine to form an IMPG-matrix that surrounds the photoreceptors? Why do IMPG1 and IMPG2 require each other to develop a healthy IPM? What is the exact size and shape of the IMPG-matrix?

Scientific illustration showing cross-sections of the retina with immunostaining for PNA, IMPG1, and IMPG2, highlighting cellular and structural details including the outer segment, inner segment, and outer plexiform layer.

Immunofluorescence technique was used to detect the localization of IMPG1 and IMPG2 in the retina through confocal microscopy.

3D reconstruction of a single cone photoreceptor in wild-type retina flat-mount, stained with PNA (red), IMPG1 (green), IMPG2 (magenta), and DAPI (blue).

3D reconstruction of the flat-mount retina from wild-type, IMPG1, and IMPG2 KO mice stained with PNA (red), IMPG1 (green), Gat2 (magenta), and DAPI (blue).

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Role of the IPM in retinal health and disease

The exchange of nutrients and molecules between the photoreceptors and the RPE takes place through the IPM. Our goal is to understand the role of the IPM in the diffusion of molecules within the photoreceptors-IPM-RPE complex in health and disease. Some of our questions extend to understand if the IPM aging alters its functional properties and how the IPM contributes to the disease mechanism of blinding diseases.

A diagram illustrating the effects of RPE on gene expression levels in retina and RPE, comparing IMPG2-KO and WT samples, using heatmaps with a color scale from blue to red. The illustration shows a cell with labeled RPE and retina, and molecular structures representing IMPG1 accumulation.

Metabolomics studies have revealed metabolic changes in the retina and RPE of mice with an affected interphotoreceptor matrix.

Microscopic images comparing wild-type and IMPG2 knockout tissues, showing differences in cell structures and microvilli appearance.

Electron microscopy revealed changes in the extracellular matrix of mutant mice.

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Mutations in IMPG1 or IMPG2 genes can cause blinding conditions such as subretinal lesions or retinitis pigmentosa. We are developing adenovirus-based gene therapies to ameliorate or cure these genetic defects. Our goal is to evaluate the efficacy of these therapies in treating IMPG-related pathologies using mouse models that reproduce the genetic defects found in humans.

In addition, we are investigating drugs targeting the IPM as a potential therapeutic for ocular diseases.

Therapeutics

Diagram showing genetic material including cDNA, shRNA, and gRNA, followed by a virus packaging process and subretinal injection into the eye, with a yellow-highlighted area in the eye indicating the injection site.

Gene therapy workflow

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Computational model of IPM

Scientific graphs comparing FMM and NM algorithms, including 3D response surfaces and line plots showing active rhodopsin molecule counts over time with varying stimulus duration and intensity.

Our objective is to create mathematical models that can explain the intricate fluid dynamics that occur within the IPM. These models will help us better comprehend the processes taking place inside the IPM. Additionally, we plan to simulate the movement of nutrients within the IPM and use this data to predict the mechanisms behind diseases resulting from aberrant IPM.

Differential equations are used to simulate the response of a single photoreceptor to light, using MATLAB.