Raju V. S. Rajala, PhDRaju

Professor of Physiology

M.G. McCool Professor of Ophthalmology

Adjunct Professor of Cell Biology

Adjunct Professor of Cell Biology and Oklahoma Center for Neuroscience

Member, Harold Hamm Diabetes Center

Special Interests

Neuroprotective survival pathways 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.

Phosphoinositide signaling in the neuroprotection of the retina.

Adapter proteins in recruiting the signaling complexes to mediate photoreceptor neuroprotection.

Training

  •     PhD, Biochemistry, Andhra University, India
  •     Postdoctoral Training, Molecular Biology, University of Saskatchewan, Saskatoon, Canada

 
Research Interests

  • Retinal Metabolism
  • Lipid nanotechnology

Research Summary

Pyruvate kinases and retinal metabolism

Vertebrate photoreceptors, like cancer cells and cells in other tissues that rely on active growth, use a specific isoform of pyruvate kinase, PKM2. Glucose from the choroidal blood passes through the retinal pigment epithelium to the retina where photoreceptors convert it to lactate. Photoreceptors then export the lactate as fuel for the retinal pigment epithelium and for neighboring Müller glial cells.  Our lab is primarily interested in how glycolytic enzyme, M2 isoform of pyruvate kinase (PKM2) regulation takes place in photoreceptors, RPE and Muller cells. Loss of PKM2 in rod and cone photoreceptors resulted in retinal degeneration.  In normal retina, PKM2 is predominantly expressed in photoreceptors and a weak expression in the RPE. In aged mice and aged postmortem human retina show increased expression of PKM2 in the RPE and reduced expression in photoreceptor cells. Studies are underway in our laboratory to understand the role of PKM2 AMD and its role in other retinal cell types.

Lipid nanotechnology

The application of viruses as a carrier to deliver genes to eye tissue was successful, although unsafe. We recently 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 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 are applicable to other tissues. This discovery opens a new approach to gene therapy research. In addition, we successfully applied LPD to deliver miRNAs to attenuate complications of diabetic retinopathy. Currently, we are using these particles to deliver miRNA, lipids, drugs, and genes to retinas that are predetermined to degenerate to delay or half the degeneration.

Recent Publications

  1. 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 9:7
  2. 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.
  3. Rajala RVS, Rajala A and Wang Y (2018) Application of Lipid Nanoparticles of Retinal Degenerative Diseases. Therapies for Retinal Degeneration (Eds. Enrique J de la Rosa and Thomas G. Cotter), Royal Society of Chemists, UK, p216-229.
  4. Rajala A, Wang Y, Abcouwer SF, Gardner TW and Rajala RVS (2017) Developmental and light regulation of tumor suppressor protein PP2A in the retina. Oncotarget, 9: 1505-1523.
  5. 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.
  6. Rajala RVS and Gardner TW (2016) Burning fat fuels photoreceptors. Nature Medicine, 22:342-343.
  7. Rajala RVS, Rajala A, Kooker C, Wang Y and Anderson RE (2016) The Warburg Effect Mediator Pyruvate Kinase M2 Expression and Regulation in the Retina. Scientific Reports, 6:37727.
  8. Rajala A, Wang Y and Rajala RVS (2016) Activation of oncogenic tyrosine kinase signaling promotes insulin-receptor-mediated cone photoreceptor survival. Oncotarget, 7: 46924-46942.
  9. Wang Y, Rajala A, Cao B, Ranjo-Bishop M, Agbaga MP, Mao C and Rajala RVS (2016) Cell-specific promoters enable lipid-based nanoparticles to deliver genes to specific cells of the retina in vivo. Theranostics, 6: 1514-1527.
  10. Woodruff ML, Rajala A, Fain GL and Rajala RVS (2015) Effect of knocking down the insulin receptor on mouse rod responses. Scientific Reports, 5: 7858.
  11. Zulliger R, Naash MI, Rajala RVS, Molday RS, Azadi S (2015) Impaired association of retinal degeneration-3 with guanylate cyclase-1 and guanylate cyclase activating protein-1 leads to Leber Congenital Amaurosis-1. Journal of Biological Chemistry, 290:3488-3499.
  12. Gupta VK, Rajala A and Rajala RVS (2015) Non-canonical regulation of phosphatidylinositol 3-kinase gamma isoform activity in retinal rod photoreceptor cells. Cell Commination and Signaling,13:7.
  13. Rajala A, Wang Y, Zhu Y, Ranjo-Bishop M, Ma JX, Mao C and Rajala RVS (2014) Nanoparticle-assisted targeted delivery of eye-specific genes to eyes significantly improves the vision of blind mice in vivo. Nano Letters, 14: 5257-5263.
  14. Rajala RVS, Rajala A, Morris AJ and Anderson RE (2014) Phosphoinositides: Minor lipids make a major impact on photoreceptor cell functions. Scientific Reports, 4: 5463.
  15. Woodruff ML, Rajala A, Fain GL and Rajala RVS (2014) Modulation of mouse rod photoreceptor responses by Grb14. Journal of Biological Chemistry, 289: 358-364.
  16. Rajala RVS, Basavarajappa DK, Dighe R and Rajala A (2013) Role of tyrosine phosphorylated Grb14 BPS region on insulin receptor and protein tyrosine phosphatase-1B. Cell Communication and Signaling, 11: 96.

Click here for a list of this investigator's publications.

Current Funding

NIH/NEI R01EY00871: Studies on phosphoinositide signaling in the retina (PI).

04/01/2016-03/31/2021

NIH/NEI R01 EY020582: Regulation of retinal cell death in diabetes (Consortium PI)

09/01/2015-08/31/2019 (PIs: Gardner and Abcouwer)

NIH/NEI 1R01EY026970-01A1: Muller glia in disease and stress (Collaborator)

09/01/2017-05/31/2022 (PI: Le Y).

Presbyterian Health Foundation: Application of 3D Bioprinting to study the Mechanisms of Age-related Macular Degeneration (PI)

12/01/2018-11/30/2019

Funding Sources
National Institutes of Health/National Eye Institute