Venkatakrishna Rao Jala, Ph.D.

Education:

B.S., Silver Jubilee Govt. College, SKD University, Kurnool, AP, INDIA
Integrated Ph.D. (MS+PhD): Indian Institute of Science, Bangalore, INDIA, 2002
Postdoctoral Fellowship, University of Louisville, Louisville, KY, 2001

Curriculum Vitae

Current Positions:

Assistant Professor, Department of Microbiology and Immunology, University of Louisville School of Medicine
Member, Immuno-Oncology Program, James Graham Brown Cancer Center
Member, Tumor Immunobiology, University of Louisville

Contact Information:

Clinical Translational Research Building, Room 323
University of Louisville
505 Hancock St.
Louisville, KY 40202, USA
Phone 502-852-5523
Fax 502-852-2123

Email: jvrao001@louisville.edu

Website:

http://louisville.edu/medicine/departments/microbiology/faculty/jala

Research Description

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 a 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, Alzheimers, 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 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 in importance, because they are involved in inflammation and autoimmune diseases, including 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 that lack of the CCR2-CCL2 axis significantly reduces 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 BLT2) and chemokine decoy receptor (ACKR2, also called D6 or CCBP2 receptor) in colon cancer progression and influence on the microbiota and vice versa. Currently, we also are 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) possesses 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 have been demonstrated to have anti-inflammatory and anti-oxidant properties in vitro. The beneficial effects provided by berries varied among individuals and this inter-individual variability has been attributed to the diverse composition of gut microflora and the 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 a 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 the 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 the 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 a new level of understanding of estrogen functions in modulating lung cancer development.

Literature Cited:

  1. Singh R, Chandrashekharappa S, Bodduluri SR, Baby BV, Hegde B, Kotla NG, Hiwale AA, Saiyed T, Patel P, Vijay-Kumar M, Langille MGI, Douglas GM, Cheng X, Rouchka EC, Waigel SJ, Dryden GW, Alatassi H, Zhang HG, Haribabu B, Vemula PK, Jala VR. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nature Communications 2019 Jan 9;10(1):89. doi: 10.1038/s41467-018-07859-7. PubMed PMID: 3062686
  2. Teng Y, Ren Y, Sayed M, Hu X, Lei C, Kumar A, Hutchins E, Mu J, Deng Z, Luo C, Sundaram K, Sriwastva MK, Zhang L, Hsieh M, Reiman R, Haribabu B, Yan J, Jala VR, Miller DM, Van Keuren-Jensen K, Merchant ML, McClain CJ, Park JW, Egilmez NK, Zhang HG. Plant-derived exosomal microRNAs shape the gut microbiota. Cell Host & Microbe 2018 Nov 14;24(5):637-652.e8. doi: 10.1016/j.chom.2018.10.001. Epub 2018 Oct 25. PubMed PMID: 30449315
  3. Totiger TM, Srinivasan S, Jala VR, Lamichhane P, Dosch AR, Gaidarski AA 3rd, Joshi C, Rangappa S, Castellanos J, Vemula PK, Chen X, Kwon D, Kashikar N, VanSaun M, Merchant NB, Nagathihalli NS. Urolithin A, a novel natural compound to target PI3K/AKT/mTOR pathway in pancreatic cancer. Molecular Cancer Therapy 2019 Feb;18(2):301-11. doi: 10.1158/1535-7163.MCT-18-0464. Epub 2018 Nov 7. PubMed PMID: 30404927; PMCID: PMC6363854
  4. Bhutiani N, Li Q, Anderson CD, Gallagher HC, De Jesus M, Singh R, Jala VR, Fraig M, Gu T, Egilmez NK. Enhanced gut barrier integrity sensitizes colon cancer to immune therapy. Oncoimmunology 2018 Aug 23;7(11):e1498438. eCollection 2018. doi: 10.1080/2162402X.2018.1498438. PubMed PMID: 30377564; PMCID: PMC6204984.
  5. Bodduluri SR, Mathis S, Maturu P, Krishnan E, Satpathy SR, Chilton PM, Mitchell TC, Lira S, Locati M, Mantovani A, Jala VR*, Haribabu B*. Mast cell-dependent CD8(+) T-cell recruitment mediates immune durveillance of intestinal tumors in Apc(Min/+) mice. Cancer Immunology Research 2018 Jan 30. doi: 10.1158/2326-6066.CIR-17-0424. PubMed PMID: 29382671. (*Corresponding author)
  6. Jala VR*, Maturu P*, Bodduluri SR, Krishnan E, Mathis S, Subbarao K, Wang M, Jenson AB, Proctor ML, Rouchka EC, Knight R, Haribabu B. Leukotriene B4-receptor-1 mediated host response shapes gut microbiota and controls colon tumor progression. Oncoimmunology 2017 Aug 10;6(12):e1361593. eCollection 2017. doi: 10.1080/2162402X.2017.1361593. PubMed PMID: 29209564; PMCID: PMC5706601. (*Equally contributed)
  7. Jala VR, Bodduluri SR, Satpathy SR, Chheda Z, Sharma RK, Haribabu B. The yin and yang of leukotriene B4 mediated inflammation in cancer. Seminars in Immunology 2017 Oct;33:58-64. Review. doi: 10.1016/j.smim.2017.09.005. PubMed PMID: 28982616; PMCID: PMC5647256.
  8. Saha P, Yeoh BS, Singh R, Chandrasekar B, Vemula PK, Haribabu B, Vijay-Kumar M, Jala VR*. Gut microbiota conversion of dietary ellagic acid into bioactive phytoceutical Urolithin A inhibits heme peroxidases. PloS One 2016 Jun 2;11(6):e0156811. doi: 10.1371/journal.pone.0156811. PubMed PMID: 27254317; PMCID: PMC4890745. (*Corresponding author)
  9. Sharma RK, Chheda ZS, Das Purkayastha BP, Gomez-Gutierrez JG, Jala VR, Haribabu B. A spontaneous metastasis model reveals the significance of claudin-9 overexpression in lung cancer metastasis. Clinical & Experimental Metastasis 2016 Mar;33(3):263-75. doi: 10.1007/s10585-015-9776-4. PubMed PMID: 26669782.
  10. Satpathy SR, Jala VR, Bodduluri SR, Krishnan E, Hegde B, Hoyle GW, Fraig M, Luster AD, Haribabu B. Crystalline silica-induced leukotriene B4-dependent inflammation promotes lung tumour growth. Nature Communications 2015 Apr 29;6:7064. doi: 10.1038/ncomms8064. PubMed PMID: 25923988; PMCID: PMC4418220.
  11. Hester CM*, Jala VR,* Langille MG, Umar S, Greiner KA, Haribabu B. Fecal microbes, short chain fatty acids, and colorectal cancer across racial/ethnic groups. World Journal of Gastroenterology 2015 Mar 7;21(9):2759-69. doi: 10.3748/wjg.v21.i9.2759. PubMed PMID: 25759547; PMCID: PMC4351229. (*Equally contributed)
  12. Sharma RK, Chheda Z, Jala VR, Haribabu B. Expression of leukotriene B4 receptor-1 on CD8+ T cells is required for their migration into tumors to elicit effective antitumor immunity. Journal of Immunology 2013 Sep 15;191(6):3462-70. doi: 10.4049/jimmunol.1300967. PubMed PMID: 23960231; PMCID: PMC3815560.
  13. Kakar SS, Jala VR, Fong MY. Synergistic cytotoxic action of cisplatin and withaferin A on ovarian cancer cell lines. Biochemical & Biophysical Research Communications 2012 Jul 13;423(4):819-25. doi: 10.1016/j.bbrc.2012.06.047. PubMed PMID: 22713472; PMCID: PMC3402232.
  14. Jala VR*, Radde BN, Haribabu B, Klinge CM. Enhanced expression of G-protein coupled estrogen receptor (GPER/GPR30) in lung cancer. BMC Cancer 2012 Jul 13;12:624. doi: 10.1186/1471-2407. (Corresponding author)
  15. Spite M, Hellmann J, Tang Y, Mathis SP, Kosuri M, Bhatnagar A, Jala VR, Haribabu B. Deficiency of the leukotriene B4 receptor, BLT-1, protects against systemic insulin resistance in diet-induced obesity. Journal of Immunology 2011 Aug 15;187(4):1942-9. doi: 10.4049/jimmunol.1100196. PubMed PMID: 21742977; PMCID: PMC3150353.
  16. Cai Y, Shen X, Ding C, Qi C, Li K, Li X, Jala VR, Zhang HG, Wang T, Zheng J, Yan J. Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity. 2011 Oct 28;35(4):596-610. doi: 10.1016/j.immuni.2011.08.001. PubMed PMID: 21982596; PMCID: PMC3205267.
  17. Mathis SP, Jala VR, Lee DM, Haribabu B. Nonredundant roles for leukotriene B4 receptors BLT1 and BLT2 in inflammatory arthritis. Journal of Immunology 2010 Sep 1;185(5):3049-56. doi: 10.4049/jimmunol.1001031. PubMed PMID: 20656922. [ http://www.jimmunol.org/content/185/5/3049.long ]
  18. Jala VR*, Haribabu B*. Real-time imaging of leukotriene B(4) mediated cell migration and BLT1 interactions with beta-arrestin. Journal of Visualized Experiments 2010 Dec 23;(46). pii: 2315. doi: 10.3791/2315. PubMed PMID: 21206474; PMCID: PMC3159663. (* corresponding author)
  19. Basu S, Jala VR, Mathis S, Rajagopal ST, Del Prete A, Maturu P, Trent JO, Haribabu B. Critical role for polar residues in coupling leukotriene B4 binding to signal transduction in BLT1. Journal of Biological Chemistry 2007 Mar 30;282(13):10005-17. doi: 10.1074/jbc.M609552200. PubMed PMID: 17237498. [ http://www.jbc.org/content/282/13/10005.long ]
  20. Jala VR, Shao WH, Haribabu B. Phosphorylation-independent beta-arrestin translocation and internalization of leukotriene B4 receptors. Journal of Biological Chemistry 2005 Feb 11;280(6):4880-7. doi: 10.1074/jbc.M409821200. PubMed PMID: 15561704. [ http://www.jbc.org/content/280/6/4880.long ]
  21. Jala VR*, Galliera E*, Trent JO, Bonecchi R, Signorelli P, Lefkowitz RJ, Mantovani A, Locati M, Haribabu B. beta-Arrestin-dependent constitutive internalization of the human chemokine decoy receptor D6. Journal of Biological Chemistry 2004 Jun 11;279(24):25590-7. doi: 10.1074/jbc.M400363200. PubMed PMID: 15084596. (*Equally contributed) [ http://www.jbc.org/content/279/24/25590.long ]
  22. Jala VR, Haribabu B. Leukotrienes and atherosclerosis: new roles for old mediators. Trends in Immunology 2004 Jun;25(6):315-22. doi: 10.1016/j.it.2004.04.003. PubMed PMID: 15145321.
  23. Jala VR*, Subbarao K*, Mathis S, Suttles J, Zacharias W, Ahamed J, Ali H, Tseng MT, Haribabu B. Role of leukotriene B4 receptors in the development of atherosclerosis: potential mechanisms. Arteriosclerosis, Thrombosis & Vascular Biology 2004 Feb;24(2):369-75. doi: 10.1161/01.ATV.0000110503.16605.15. PubMed PMID: 14656734. (*Equally contributed)

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