Giridhar Akkaraju, Ph.D.

VIRUS PATHOGENESIS HCV is a very successful pathogen infecting over 170 million people worldwide. Chronic HCV infection is established in over 85% of cases, and approximately 70% of these individuals develop cirrhosis or hepatocellular carcinoma. There is currently no vaccine and while new drugs have been developed that successfully control virus replication, the potential emergence of drug resistant strains is a major problem. Understanding how HCV and other RNA viruses like Zika Virus, evade the antiviral response will contribute towards the development of improved treatment strategies. This is the focus of one of the research projects in my laboratory. One of the tools HCV uses against the cell is a virally encoded signal transduction modulator protein NS5A, which binds to several proteins including dsRNA-dependent protein kinase (PKR) and inhibits its activation. NS5A expression also prevents the expression of cytokines like Interferon-beta (IFN-beta), which is required to induce the antiviral state in the infected cell. This allows the virus to persist in the infected cells of the liver. We are interested in understanding the mechanism by which NS5A (and proteins with related function in Zika Virus) inhibits expression of IFN-beta. We are also engaged in the identification of drugs that can inhibit these proteins from natural products.

CANCER DRUG DEVELOPMENT Targeted therapy of cancer attempts to directly attack the vulnerabilities present in the cancer cell. Traditional cancer therapies using radiation and chemotherapy kill all rapidly dividing cells in the body leading to severe side effects. We are working on testing a new molecule containing a DNA-methylating agent conjugated to a steroid hormone (Dr. Sridhar Varadarajan, UNC Wilmington, Chemistry). Binding of the hormone to its receptor leads to its transport to the nucleus where the receptor binds to the DNA. This brings the DNA-methylating agent in close proximity to the DNA where it can modify adenine residues and induce cell death. In effect, the steroid hormone acts as a “Trojan horse” and delivers a deadly cargo to the target cells. Since many steroid-dependent cancers overexpress the hormone receptors (e.g., estrogen receptor expressing breast cancer cells) this increases the specificity of the drug and reduces the side effects.

NANOMATERIALS AS DRUG-DELIVERY AND DIAGNOSTIC AGENTS In collaboration with Dr. Jeffrey Coffer of the TCU Chemistry Department, we are testing a modified form of silicon (Porous Silicon-PSi) for use in a variety of applications. PSi is biocompatible and capable of a versatile range of surface modifications that can modify its properties, including its solubility and its affinity for payload molecules. Currently, we are trying to use these surface-modified Silicon microparticles for delivery of useful therapeutic agents (such as DNA and cytotoxic drugs) to target cells.
In collaboration with Dr. Anton Naumov (TCU Physics Department), we are exploring the use of graphene-derived quantum dots in the detection and treatment of cancer.

ANTI-INFLAMMATORIES AS TREATMENTS FOR ALZHEIMER’S DISEASE AND TRAUMATIC BRAIN INJURY A variety of projects in the lab explore the role of novel compounds as anti-inflammatories. Inflammation has been singled out as an important causative event in neurological damage; either from disease conditions (such as Alzheimer’s) or from traumatic events. We are evaluating compounds synthesized by our collaborators (Dr. Kayla Green, TCU Chemistry Department) in the reduction of TNF-alpha mediated inflammatory signaling and the reduction of Reactive Oxygen Species (ROS) in neurological damage.

How does one prepare a student for a world where information content grows at an exponential rate? While a certain foundation of knowledge is essential to make sense of all this information, my approach is to give students the tools they need to go out and acquire relevant information when necessary, and to critically analyze it when appropriate.

In all my courses, I focus on the methodology by which this new information is obtained. My students do so by reading the primary literature where these discoveries are first described. This also gives them an idea of the techniques used in that particular field of study.
Along the way, I try to instill and sense of wonder and excitement to draw students into topics that I find fascinating.

For example, in Virology we do a classroom exercise called, “How to be a virologist”, where students come up with questions they would ask if presented with an unknown virus.

As I tell students in my classes, I can’t “teach” them anything…but I can show them how to learn.

• Kishton, R. J., Miller, S. E., Perry, H., Lynch, T., Patel, M.*, Gore, V. K., Akkaraju, G. R., Varadarajan, S, DNA site-specific N3-adenine methylation targeted to estrogen receptor-positive cells. (2011) Bioorganic & Medicinal Chemistry, 19, 5093-5102.

• Enhancement of the Antioxidant Activity and Neurotherapeutic Features through Pyridol Addition to Tetraazamacrocyclic Molecules. Johnston, H.M.**, Pota, K.**, Barnett, M. M.*, Kinsinger, O.*, Braden, P.*, Schwartz, T.M., Hoffer, E., Sadagopan, N.*, Nguyen, N., Yu, Y., Gonzalez, P., Tircso, G., Wu, H., Akkaraju, G., Chumley, M., and Green, K.N. Inorganic Chem., 2019, 58, 16771-16784.

• Doped Graphene Quantum Dots for Intracellular Multicolor Imaging and Cancer Detections. Campbell, E.**, Hasan, Md. T.**, Rodriguez, R. G., Akkaraju, G. R., and Naumov, A. V. ACS Biomaterials Science Engineering, 2019, 5, 4671-4682.

• Formation of Platinum Nanocrystals on Silicon Nanotubes and Corresponding Anti-Cancer Activity In Vitro. Nguyen, T.L.**, Akkaraju, G.R., and Coffer, J.L. ACS Applied Bio Materials 2020 3, 208-216.
  

• The Hepatitis C virus non-structural Protein NS5A attenuates virus-induced activation of the Interferon-beta promoter by inhibiting the activation of transcription factor NF-kB. (2015) Akkaraju, G. R., Richards, J.M*., Hoge, E.M*. and Vouzas, A*. Annual Meeting of the American Society for Virology, London ON.

• Coffer, J. L., Le, N. T., & Akkaraju, G. R. (2019). Formation of Platinum Nanocrystals on Silicon Nanotubes and In Vitro Anti-Cancer Activity of the Composites. 235th Electrochemical Society Meeting. Dallas, TX.

Honors

• TCU Wassenich Award for Mentoring (2020)
• Mortar Board Preferred Professor 
• TCU Pan-Hellenic Professor of the Year

Awards

• J.V. Roach Honors College Professor of the Year (2009)

Grants

National Institutes of Health R15 (1 R15 GM123463-01A1), Targeting oxidative stress in neurodegeneration using pyridol-derived small molecules, 06/2018 –05/2021, $378,914, PIs: Dr. Kayla Green (TCU), Dr. Giri Akkaraju (TCU), and Dr. Michael Chumley (TCU)

• Member, American Society for Virology