Raju V. S. Rajala, PhD
Professor of Physiology
M.G. McCool Professor of Ophthalmology
Edith Kinney Gaylord Presidential Professor
Professor of Physiology
Director of Research, Physiology
Adjunct Professor of Cell Biology
Member, Harold Hamm Diabetes Center
405 271 8255
The principal thrust of my current research is to redefine our understanding of neurodegenerative diseases of the retina. Light-sensing photoreceptor cells in the retina are terminally differentiated. Thus, once they are lost, they cannot regenerate, making the development of potential therapies infinitely more challenging. As a result, currently available treatments can only delay vision loss; they cannot prevent it. Our aims involve developing innovative approaches to prevent visual loss through manipulation of metabolic reprogramming, use of lipid nanotechnology, stem cell implantation, and activation of endogenous neuroprotective pathways. Translational application of our work to Phase I human studies is our ultimate goal. Our research also focuses on the parallels between cancer metabolism and photoreceptor degenerative diseases.
1. Signaling Roles of Phosphoinositide Lipids in the Retina. Phosphoinositides (also known as phosphatidylinositol phosphates, or PIPs) are universal signaling molecules that directly interact with membrane proteins or with cytosolic proteins containing domains that directly bind PIPs and are recruited to cell membranes. Through the activities of phosphoinositide kinases and phosphoinositide phosphatases, seven distinct phosphoinositide lipid molecules are formed from the parent molecule, phosphatidylinositol. PIP signals regulate a wide range of cellular functions, including cytoskeletal assembly, membrane budding and fusion, ciliogenesis, vesicular transport, and signal transduction. Changes in the expression and activity of PIP-kinases and PIP-phosphatases have been implicated in retinal degeneration. Our lab is investigating the function and mechanism of activation of PIP-modifying enzymes/phosphatases and further unraveling PIP regulation and function in the different cell types of the retina.
2. 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.
3. 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 contributes to gliotic responses and scar formation but also shows 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.
4. Endogenous Neuroprotective Pathways in the Retina. Every day, our eyes are exposed to copious amounts of light, and the endogenous neuroprotective pathways in the retina act as molecular sunglasses. Several neuroprotective pathways have been identified in the retina in response to stress; however, the pathway(s) that provide daily neuroprotection is yet to be determined. The insulin-like growth factor 1 receptor (IGF-1R) is a receptor tyrosine kinase that mediates the actions of IGF1, which binds with high affinity and is expressed in the retina and photoreceptor cells. Human carriers of homozygous mutations associated with reduced expression of the IGF-1R ligand, Igf1 gene, have mental retardation and deafness, which are associated with severe prenatal growth retardation, postnatal growth failure, and microcephaly. Global IGF-1 KO mice have been shown to have an age-related visual loss in addition to congenital deafness. Our recent studies showed that loss of IGF-1R in photoreceptor cells resulted in retinal degeneration. Therefore, understanding the mechanism(s) involved in the activation and deactivation of IGF-1R should have implications for retinitis pigmentosa, age-related macular degeneration, and Usher syndrome. We are using retina cell-specific knockout models of IGF-1R and IGF-1 to define the mechanism of IGF-1R-mediated endogenous neuroprotective pathways.
5. Non-canonical Insulin Receptor Signaling Pathway in Photoreceptor Cells. Insulin receptors (IR) and insulin signaling proteins are widely distributed throughout the central nervous (CNS) system. Dysregulation of IR signaling in the CNS has been linked to the pathogenesis of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. We discovered that IR signaling in rods is controlled by growth factor receptor-bound protein 14 (Grb14), an upstream regulator of the IR, and requires photobleaching of rhodopsin for membrane targeting. Grb14 prevents IR dephosphorylation by protein tyrosine phosphatase 1B (PTP1B), a tyrosine phosphatase specific to the IR. Our recent studies established a down-regulation of IR signaling due to increased retinal PTP1B activity in animal models of retinitis pigmentosa, diabetic retinopathy, and Leber Congenital Amaurosis. Studies are underway in our laboratory to target PTP1B in these disease models. Our new and innovative approaches to target PTP1B will facilitate the future translational application of our work to apply our findings to the clinical care of human retinal degenerative diseases.
6. Application of Lipid Nanoparticles for Retinal Degenerative Diseases. The application of viruses as a carrier to deliver genes to eye tissue was successful, although unsafe. We have created an artificial virus using a nanoparticle, liposome-protamine-DNA complex (LPD), modified with a cell-permeable peptide and a nuclear localization signaling (NLS) peptide, to deliver a functional gene for the treatment of eye disease. We showed for the first time that LPD promotes efficient delivery in a cell-specific manner, and long-term expression of the Rpe65 gene to mice lacking Rpe65 protein, leading to in vivo correction of blindness. Thus, LPD nanoparticles could provide a promising, efficient, non-viral method of gene delivery with clinical applications in eye disease treatment that apply to other tissues. In addition, we successfully applied LPD to deliver miRNA-184 to repress Wnt-mediated ischemia-induced retinal neovascularization (oxygen-induced retinopathy). Currently, we are using these particles to deliver miRNA, lipids, drugs, and genes to retinas that are predetermined to degenerate to delay or halt the degeneration.
- PhD, Biochemistry, Andhra University, India
- Postdoctoral Training, Molecular Biology, University of Saskatchewan, Saskatoon, Canada
- Phosphoinositide signaling in the neuroprotection of the retina.
- Neuroprotective survival pathways are regulated by receptor and non-receptor tyrosine kinases and receptor and non-receptor tyrosine phosphatases.
- Cross communication between rhodopsin and tyrosine kinase/phosphatase signaling in photoreceptors.
- Adapter proteins in recruiting the signaling complexes to mediate photoreceptor neuroprotection.
- Retinal Metabolism
- Lipid nanotechnology/3D bioprinting
- NIH/NEI R01EY00871: Studies on Phosphoinositide Signaling in the Retina (PI).
- NIH/NEI R01EY030024: Neuroprotection Mechanism for Photoreceptors (PI).
- BrightFocus Foundation: M2-Isoform of Pyruvate Kinase is a Biomarker for Age-Related Macular Degeneration (PI).
- Oklahoma Center for Adult Stem Cell Research: PKM2 promotes the stemness of Muller Glial cells in the retina (PI).
- NIH/NEI P30EY021725 Core Grant for Vision Research (Module Director, Live Animal Imaging and Analysis Core).
- Funding Sources
- National Institutes of Health/National Eye Institute
1. Rajala RVS (2021) Signaling roles of phosphoinositides in the retina. Journal of Lipid Research, 62:100041.
2. Shang P, Stepicheva N, Teel K, McCauley A, Fitting C.S, Hose S, Grebe R, Yazdankhah M, Ghosh S, Liu H, Strizhakova A, Weiss J, Bhutto I.A, Lutty GA, Jayagopal A, Qian J, Sahel JA, Samuel Zigler J Jr, Handa JT, Sergeev Y, Rajala RVS, Watkins S, Sinha D (2021). βA3/A1-crystallin regulates apical polarity and EGFR endocytosis in retinal-pigmented epithelial cells. Nature-Communications Biology, 4: 850.
3. Rajala A, He F, Anderson RE, Wensel TG and Rajala RVS (2020) Loss of class III phosphoinositide 3-kinase Vps34 results in cone degeneration. Biology, 9: 384.
4. Rajala RVS (2020) Aerobic glycolysis in the retina: Functional roles of pyruvate kinase isoforms. Frontiers in Cell and Developmental Biology 8: 266.
5. Rajala A, Soni K and Rajala RVS (2020) Metabolic and non-metabolic roles of pyruvate kinase M2 isoform in diabetic retinopathy. Scientific Reports 10:7456.
6. Lee SY, Surbeck JW, Drake M, Saunders A, Jin HD, Shah V and Rajala RVS (2020) Increased glial fibrillary acid protein and vimentin in the vitreous fluid as a biomarker for proliferative vitreoretinopathy. Investigative Ophthalmology and Visual Science 61: 22.
7. Rajala RVS (2019) Therapeutic benefits from nanoparticles: The potential significance of nanoscience in retinal degenerative diseases. Journal of Molecular Biology and Therapeutics 1: 44-55.
8. Losiewicz MK, Elghazi L, Fingar DC, Rajala RVS, Lentz SI, Fort PE, Abcouwer SF, Gardner TW (2020) mTORC1 and mTORC2 expression in inner retinal neurons and glial cells. Experimental Eye Research, 197: 108131.
9. Rajala A, Wang Y, Soni K, and Rajala RVS (2018) Pyruvate kinase M2 isoform deletion in cone photoreceptors results in age-related cone degeneration. Cell Death and Disease 9:737.
10. Rajala A, Wang Y, Brush RS, Tsantilas K, Jankowski CSR, Lindsay KJ, Linton JD, Hurley JB, Anderson RE and Rajala RVS (2018) Pyruvate kinase M2 regulates photoreceptor structure, function, and viability. Cell Death and Disease 9:240.
11. Chen Q, Qiu F, Zhou K, Matlock, GH, Takahashi Y, Rajala RVS, Yang Y, Moran E, and Ma JX (2017). Pathogenic Role of MicroRNA-21 in Diabetic Retinopathy through Down-regulation of PPARα. Diabetes, 66: 1671-1682.
12. Rajala RVS and Gardner TW (2016) Burning fat fuels photoreceptors. Nature Medicine, 22:342-343.