Venkatakrishna Rao Jala, Ph.D.

Venkatakrishna Rao Jala, Ph.D.

Research Interests

The G-protein-coupled receptor (GPCR) represent a large super family of seven treansmembrane-spanning proteins comprised of an estimated 600-1,000 members and is the largest known class of molecular targets with proven therapeutic value.  GPCRs are instrumental in the transmission of a wide range of chemical messages from the extracellular environment to the interior of the cell. GPCRs have been implicated in a wide range of disorders including allergies, cardiovascular dysfunction, depression, obesity, cancer, pain, arthritis, diabetes, AIDS and various central nervous system disorders.

1. Elucidating the signal transduction pathways of estrogen-GPR30 (novel estrogen binding receptor) and understanding their structure-function relationships in invitro and invivo models.

Estrogen (17beta-estrodiol, E2) is an ovarian steroid hormone essential for the growth of both normal and transformed epithelial cells during pregnancy. Estrogens are also known to promote various types of cancers including breast, endometrial cancer and ovarian cancers. Estrogen mediates its effects through two well characterized nuclear receptors, estrogen receptor a (ERalpha) and estrogen receptor b (ERbeta). Tamoxifen, a selective ER modulator (a selective antagonist for ERalpha) is a widely used drug to treat breast cancer. However, long term use of the drug leads to several complications including increased risk of developing endometrial and lung cancer. It has been observed that 1 in 4 patients do not respond to tamoxifen despite being positive for ERs. There is now considerable evidence to suggest that some of the estrogen actions are independent of ERalpha and ERbeta.  Recent discovery of GPR30, which suffices the membrane actions of E2 (also known as DRY12, FEG-1, LERGU, LyGPR, CMKRL2, LERGU2 and GPCR-Br) adds further complexity to estrogen biology. The role of this receptor has been implicated in several cancers, including breast, ovarian, endometrial and thyroid cancer. Our interests are to determine the structure-function relationships of estrogen-GPR30 and their role in development of lung cancer.

 

Collaboration projects with Prof. Haribabu Bodduluri:

2. Elucidating the role of chemokine receptors in the development of inflammatory diseases including atherosclerosis, arthritis and 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. In recent years, chemokines and their receptors have grown in importance, because they are involved in inflammation and autoimmune diseases, includes AIDS, atherosclerosis, arthritis, cancer and asthma etc. Chemokines and their receptors are now known to play a crucial part in directing the movement of mononuclear cells throughout the body, engendering the adaptive immune response and contributing to the pathogenesis of a variety of diseases. Chemokine receptors are some of the most tractable drug targets in the huge battery of molecules that regulate inflammation and immunity. Our interests include, determining the structure-function relationships of leukotriene receptor 1 and 2 (BLT1 and BLT2) and D6 chemokine receptors (Decoy) and their in the development of atherosclerosis, arthritis and cancer usingin vitroandin vivomodels. We recently started looking at role of inflammation in colon cancer development and modulation of microbiome in a host dependent manner.

3.Host-Microbiota interactions in colon cancer and diabetes:The complex nature of the humangut microbiotaand its relevance to human health and disease is at an 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. We have identified the major role of microbiota and one of the GPCR called leukotriene B4 receptor1 (BLT1) in controlling colon cancer development in pre-clinical models in collaboration with Dr. Bodduluri. There are some epidemiological evidences to suggest the relationships between colon cancer and diabetes. However, there were not many efforts were dedicated to understand the molecular mechanisms or development of the pre-clinical models to study these inter-relationships. Despite knowing the role of microbiota in these disease conditions separately, there were no studies reported until now to examine the influence of host and environmental factors in these disease models. One of my major interests include understanding the influence of gut microbiota in the development of inflammatory disorders (colon cancer and diabetes) and the role of host or disease in modulating/reshaping the gut microbiota or vice versa, i.e., to define cause or consequence. We adopted and improvised the complete protocols to perform microbial sequencing on Roche 454 Jr Sequencing platform as well as metagenomic analysis at University of Louisville. We have completed several microbiome projects in collaboration with several groups. To list some of these include, but not limited to (a) determine the differential microbiome pattern between various ethinc groups (Caucasian, African-American, American-Indian) to identify the disease susceptible status based on microbiota patterns and (b) identification of small amounts of lung pathogens in infectious disease from nasal and nasopharyngeal swabs.

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.