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 2025

Experiments in this Retina Research Foundation renewal proposal build off of metabolomic profiling data generated during the 2024 funding period to continue to focus on metabolic changes in Muller glia and how they regulate Muller glia reprogramming and regenerative responses. These results will be significant because proteins and metabolites that we identify can then potentially serve as foundations for the development of new therapeutic approaches aimed at stimulating intrinsic regeneration in the human retina.

Metabolic reprogramming is common during development and has been implicated in regeneration of some tissues and organs, but not yet assessed in the retina.  Indeed, metabolic shifts have been implicated in a number of regenerative responses; however, there is almost no knowledge of the metabolic state of quiescent Muller glia and how this changes during injury and regenerative responses, nor whether specific metabolites facilitate reprogramming and regenerative responses.  Dr. Gross hypothesizes that metabolic reprogramming is a key factor in the ability of Muller glia to transition to a regenerative state. Using metabolome data, his team will determine if top metabolites generated after retinal injury are necessary and/or sufficient to stimulate intrinsic retinal regeneration.

Specific Aims: In 2025 Dr. Gross will assess specific metabolites, and the pathways that generate them, to determine if they play a direct role in metabolic reprogramming of Muller glia after retinal injury.

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

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.