Venkatakrishna Rao Jala, Ph.D.

Venkatakrishna Rao Jala, Ph.D.

Research Interests

 

Dr. Jala’s research interest is in understanding the regulation of Inflammation, Gut microbiota and Microbial metabolites in cancer development, especially colon cancer. Colorectal cancer (CRC) is strongly associated with inflammation accompanied by increased infiltration of leukocytes. Inflammation is a resultant of host immune response to an injury, infections or illness and considered as double-edged sword. The initial response to infections/injuries is handled (cleared) by immune systems by generating so-called acute inflammatory reaction. The major problem arises when the inflammation persists (chronic inflammation) and promotes disease conditions. The chronic inflammation is a major underlying cause for many of the diseases including but not limited to cancer, arthritis, cardiovascular diseases, diabetes, asthma, Alzheimer, etc. The mechanisms involved in maintaining balance between the good vs bad inflammatory conditions in various inflammatory disorders are unknown and a major topic of research in current biology.

The complex nature of the human gut microbiota and its relevance to human health and disease is at a very early stage of investigation. It is becoming very clear that changes in the environment, diet and genetic factors greatly influence human microbiota contributing to the modulation of disease progression. Dr. Jala’s laboratory focuses on determining the role of chemokine receptors, gut microbiota and interaction of microbial metabolites in colon cancer. We utilize several genetically altered transgenic/compound (knockout/conditional expression of interested genes) pre-clinical mouse models, cellular and molecular models and next generation sequencing methods to understand the colon cancer progression.

Chemokine receptors-Gut microbiota and colon cancer: The chemokines (chemotactic chemokines) are a family of small proteins or lipids known for their ability to control cell migration in the body. Their receptors belong to the class A subfamily of G protein-coupled receptors (GPCRs). In recent years, chemokines and their receptors have grown their importance, because they are involved in inflammation and autoimmune diseases, includes AIDS, atherosclerosis, arthritis, cancer and asthma etc. Chemokine receptors are some of the most tractable drug targets in the huge battery of molecules that regulate inflammation and immunity. For example CCR2, a seven transmembrane GPCR, mediates several biological functions including chemotaxis of leukocytes upon binding to its ligand, CCL2 (MCP1). Elevated expression of CCL2 in tumor cells is very well correlated with increased metastasis and poor prognosis in several types of human cancers. We also determined lack of CCR2-CCL2 axis significantly reduce the colon tumorigenesis in mouse models. Dr. Jala’s laboratory investigates the role of CCL2-CCR2 axis in balancing the inter-relationship between immune system and microbiota in colon tumorigenesis. Determining the molecular, cellular mechanisms and complex inter-relationship between immune system-microbiota in the context of cancer will have a strong impact on our basic understanding of intestinal carcinogenesis as well as potential for developing novel therapeutic strategies. In collaboration with Dr. Bodduluri, we also investigate the role of leukotrienes and their receptors (BLT1 and BLT1) and chemokine decoy receptor (ACKR2, also called as D6 or CCBP2 receptor) in colon cancer progression and influence on the microbiota and vice versa. Currently, we are also focusing on determining the differential microbiome pattern between various ethnic groups (Caucasian, African-American, American-Indian) to identify the disease susceptible status based on microbiota patterns in collaboration with Kansas University.

Microbial metabolites and colon cancer: Epidemiological data strongly links Western diet with colon cancer progression. The diet-based approaches for colon cancer prevention have taken a major precedence in recent years. Among the various groups of food products with anti-cancer properties, natural products derived from colored berries and pomegranates have received considerable attention. In particular, the health benefits of pomegranates have been attributed to their ellagitanins and ellagic acid (EA). Several reports suggest that ellagic acid (EA) possess a plethora of biological properties such as anti-oxidant, anti-inflammatory and cancer protective activities. However, the major mechanisms involved in this process are unknown. Urolithins (dibenzopyran-6-one derivatives) are gut microbial metabolite products derived from EA, ellagitannins and has been demonstrated to have anti-inflammatory and anti-oxidant properties in vitro. The beneficial effects provided by berries varied among each individuals and this inter-individual variability has been attributed to diverse composition of gut microflora and their metabolic capabilities of the EAs. Our laboratory focuses on   determining the potential mechanisms and special delivery methods of diet-based use of Urolithins in preventing the incidence and progression of inflammation promoted colon cancerby modulating gut microbiota and suppressing inflammation.

Estrogens-Lung cancer: Lung cancer is the leading cause of cancer-related deaths. Epidemiologic data indicate that women have a higher risk of lung adenocarcinoma and there is significant increase in serum free 17β-estradiol (E2) levels in lung cancer patients. However, the molecular mechanisms of estrogen actions in lung cancer progression are largely unknown. 17-β estradiol (E2) mediates its actions via two known classical estrogen receptors, ERα, ERβ as well as recently discovered G-protein coupled estrogen receptor (GPER). Recently, I have identified the elevated levels of GPER in human lung cancer samples (with score 2-3+) in > 76% (out of 87 cases) indicating its strong correlation of GPER to lung cancer. We are currently investigating the physiological role of GPER and E2 in lung cancer development using comprehensive molecular and genetic approaches (knockout and conditional transgenic mice) by implanting E2 and inhibitors. We also utilize the computational dynamic modeling, cell biological methods (in vitro) to define structure-function relationships and identify the novel agonists/antagonists to provide new level of understanding of estrogen functions in modulating lung cancer development.

SELECTED PUBLICATIONS

1.  Jala, V.R.*,Radde, B.N., Haribabu, B., and Klinge, C.M. 2012. Enhanced expression of G-protein coupled estrogen receptor (GPER/GPR30) in lung cancer. BMC Cancer 12:624.

2.   Kakar, S.S.,Jala, V.R.,and Fong, M.Y. 2012. Synergistic cytotoxic action of cisplatin and withaferin A on ovarian cancer cell lines. Biochem Biophys Res Commun 423:819-825.

3.  Cai, Y., Shen, X., Ding, C., Qi, C., Li, K., Li, X.,Jala, V.R.,Zhang, H.G., Wang, T., Zheng, J., et al. 2011. Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity 35:596-610.

4.   Spite, M., Hellmann, J., Tang, Y., Mathis, S.P., Kosuri, M., Bhatnagar, A.,Jala, V.R., and Haribabu, B. 2011. Deficiency of the leukotriene B4 receptor, BLT-1, protects against systemic insulin resistance in diet-induced obesity. J Immunol 187:1942-1949.

5.  Jala, V.R.,and Haribabu, B. 2010. Real-time imaging of leukotriene B(4) mediated cell migration and BLT1 interactions with beta-arrestin. J Vis Exp

6.   Mathis, S.P.,Jala, V.R.,Lee, D.M., and Haribabu, B. 2010. Nonredundant roles for leukotriene B4 receptors BLT1 and BLT2 in inflammatory arthritis. J Immunol 185:3049-3056.

7.   Nasser, M.W., Raghuwanshi, S.K., Grant, D.J.,Jala, V.R., Rajarathnam, K., and Richardson, R.M. 2009. Differential activation and regulation of CXCR1 and CXCR2 by CXCL8 monomer and dimer. J Immunol 183:3425-3432.

8.   Salogni, L., Musso, T., Bosisio, D., Mirolo, M.,Jala, V.R.,Haribabu, B., Locati, M., and Sozzani, S. 2009. Activin A induces dendritic cell migration through the polarized release of CXC chemokine ligands 12 and 14. Blood 113:5848-5856.

9.  Jala, V.R.,Shao, W.H., and Haribabu, B. 2005. Phosphorylation-independent beta-arrestin translocation and internalization of leukotriene B4 receptors. J Biol Chem 280:4880-4887.

10.Jala, V.R., and Haribabu, B. 2004. Leukotrienes and atherosclerosis: new roles for old mediators. Trends Immunol 25:315-322.