Department of Molecular Biosciences
University of Texas at Austin, Austin TX

BASIC RESEARCH PROJECT

A proteomic analysis of mitochondria-ER contact sites in Muller glia and the potential role of metabolomic changes in regulating intrinsic retinal regeneration

Research Interests

The overarching goal of  Dr. Gross’ research is to identify the molecular underpinnings of Muller glia dependent retinal regeneration. In his recent studies, he and his team focused on a previously unexplored aspect of the regenerative process – how metabolic changes facilitate Muller glia activation, reprogramming and regenerative responses.

Plans for 2026

Experiments proposed for 2026 leverage metabolomic profiling data, pharmacological assays and unique animal models that Dr. Gross’ lab generated and validated during the 2025 funding period. The team will continue to focus on the novel concept that metabolic changes in Muller glia regulate Muller glia reprogramming and regenerative responses. This question is significant because identified proteins and metabolites can potentially serve as foundations for the development of new therapeutic approaches aimed at stimulating intrinsic regeneration in the human retina.

Little is known about how metabolic changes alter the epigenomic landscape. This represents a major knowledge gap in the field and uncovering the connection between metabolic shifts and epigenetic regulation in Müller glia could provide critical insights into mechanisms underlying retinal regeneration. We hypothesize that changes in mitochondrial morphology are linked to metabolic shifts and epigenetic remodeling in Müller glia during regeneration. Dr. Cross is also investigating the effects of forcing Müller glia to shift from glycolysis toward oxidative phosphorylation and whether this alters mitochondrial morphology and induces epigenomic changes.

Specific Aims: We will continue to assess specific metabolites and the pathways that generate them, how mitochondrial morphology influences metabolic process and the link between metabolic shifts and epigenetic changes, with the overarching goal to determine how these processes influence Muller glia reprogramming and retinal regeneration.

Progress in 2025

Dr. Gross’ metabolomic analysis identified 472 metabolites that were significantly up- or downregulated in the retina across different time points post injury. The identified metabolites are involved in various metabolic pathways ranging from lipid biosynthesis to carbohydrate metabolism. The Gross lab hypothesized that a metabolic shift from glycolysis to oxidative phosphorylation occurs following injury, triggering Müller glia to reprogram. To explore this, the team focused on metabolites associated with glycolysis, gluconeogenesis, pyruvate metabolism, the TCA cycle, and oxidative phosphorylation, identifying a role for these components in facilitating Muller glia reprogramming. They also established a gfap:mito-GFP transgenic line which enables them to visualize mitochondrial morphology and distribution in Müller glia following injury.

Progress in 2024

Dr. Gross proposed to build off of proteomic and RNA-Seq data generated during the 2023 funding period to continue to focus on metabolic changes in Muller glia and how they regulate Muller glia reprogramming and regenerative responses.

During the 2024 funding period Dr. Gross’ laboratory performed targeted metabolomic analyses of quiescent and injured retinae, with damage achieved using a photoreceptor degeneration paradigm.  We profiled several time points post-injury as well as after treatment with DCA (dichloroacetic acid), which blocks pyruvate dehydrogenase kinase and thereby increases the rate of glucose oxidation, shifting the metabolic profile of cells towards oxidative phosphorylation at the expense of glycolysis.

Progress in 2023

During the 2023 funding period, Dr. Gross performed targeted proteomic analyses of quiescent and injury-responsive Muller glia that were activated using a photoreceptor degeneration paradigm. Our preliminary data identified enriched proteins associated with Muller glia reactivity and metabolic activity in injury-responsive samples. In parallel, using RNA-sequencing of the same Muller glia populations, transcripts encoding proteins that function to during metabolism or to modulate metabolic processes were the most significantly upregulated in injury-responsive Muller glia. These data strongly support the hypothesis that retinal injury modulates metabolic activity in Muller glia.