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Raju Rajala

Mediators of the Warburg Effect in Retinal Health and Disease. The Warburg Effect is the enhanced conversion of glucose to lactate observed in tumor and retinal cells, even in the presence of normal levels of oxygen. Both tumor and retinal cells reprogram glucose for anabolic processes, which include lipid, protein, and RNA/DNA synthesis, as well as antioxidant metabolism. Three glycolytic enzymes, pyruvate kinase M2 (PKM2), lactate dehydrogenase A (LDHA), and aldolase, are involved in anabolic processes. These three enzymes work together in a coordinated manner. Understanding the interplay between these three key mediators will help us to define the checkpoints in metabolism to promote long-term retinal cell survival in retinal diseases. We are studying the role and regulation of these three proteins in photoreceptor cells, retinal pigment epithelium, and Müller cells, and a metabolic ecosystem that exists between these cell types. 

PKM2 Promotes Stemness of Müller Glial Cells in the Retina. In humans and other mammals, the neural retina does not spontaneously regenerate. Damage to the retina that kills retinal neurons results in permanent blindness. In contrast to embryonic stem cells, induced pluripotent stem cells, and embryonic/fetal retinal stem cells, Müller glial cells offer an intrinsic cellular source for regenerative strategies in the retina. Müller glia are radial glial cells within the retina that maintain retinal homeostasis, buffer ion flux associated with visual perception, and form the blood/retinal barrier within the retina proper. In injured or degenerating retinas, Müller glia contribute to gliotic responses and scar formation, but also show regenerative capabilities that vary across species. In the mammalian retina, regenerative responses achieved to date remain insufficient for potential clinical applications. To achieve clinical relevance, additional intrinsic and extrinsic factors that restrict or promote regenerative responses of Müller glia in the mammalian retina must be identified. Our laboratory has found that an enzyme called pyruvate kinase M2 (PKM2) is possibly involved in the process of making adult stem cells from Müller cells. Studies are underway in our laboratory to understand the role of PKM2 in the reprogramming of Müller glial cells to photoreceptor cells. If successful, the significance of this research is potentially high, as it not only benefits blinding disorders, but should have broad applicability to other neurological diseases, such as Alzheimer’s and Parkinson’s diseases.