Haribabu Bodduluri, Ph.D.

Haribabu Bodduluri, Ph.D.

Research Interests

Research in Bodduluri laboratory is focused on identifying how chemokines control leukocyte migration and tumor development with particular emphasis on leukotriene B4 and its receptors BLT1 and BLT2. Over the last decade, we developed mouse models and generated novel reagents to examine the function and regulation of BLT1 and BLT2. These models facilitated the identification that BLT1 is a critical mediator of inflammatory diseases including asthma, atherosclerosis, arthritis and other autoimmune diseases as well as sleep apnea promoted atherogenesis and insulin resistance during diet induced obesity.

Our studies on cancer use mouse models of spontaneous cancers of lung and colon that were crossed onto mice deficient in BLT. These experiments revealed quite unexpected and exciting opportunities for novel clinical intervention of these cancers. BLT1 is an important mediator of host response to infection and immune surveillance of intestinal cancers. Our studies showed that exposure to crystalline silica, a common agent encountered in mining and other industries strongly promotes lung cancer and absence of BLT1 protects mice from developing silicosis and reduces the lung cancer burden. Crystalline silica induces the synthesis of LTB4 from mast cells and macrophages that orchestrates neutrophil recruitment through a novel self-perpetuating cascade that results in chronic tumor promoting lung inflammation. We are currently working out mechanisms involved in this inflammatory cascade so as to develop intervention strategies to prevent silicosis and associated lung cancers.

Our recent observations in models of colon cancer suggest that absence of BLT1 reshapes the gut microbiome to promote colon cancer development. Absence of BLT1 was also found to significantly impair cytotoxic T-cell mediated anti-tumor immunity in intestinal tumors as well as in implantable melanoma. In this case mast mediated LTB4 acts to recruit CD8+ T-cells and our current studies are aimed at understanding the mechanistic implications of these findings to determine how LTB4/BLT1 axis could mediate both tumor promoting and tumor suppressive mechanisms depending on the anatomical location of the tumors. Using structure based virtual screening strategies many novel compounds that are agonists and/or antagonists to BLT1 were identified. Further studies on preclinical development of these compounds are ongoing in our laboratory.

Selected Publications:

Subbarao, K., Jala, VR, Mathis, S., Zacharias, W., Suttles, J., Ahamed, J, Ali, H., Tseng, MT. and Haribabu, B. Role of Leukotriene B4 Receptors in the Development of Atherosclerosis: Potential Mechanisms. Arterioscler Thromb Vasc Biol. 24: 369-375(2004).

Shao, WH., Del Prete, A., Bock, CB and Haribabu, B. Targeted Disruption of Leukotriene B4 Receptors BLT1 and BLT2: A Critical Role for BLT1 in Collagen-Induced Arthritis in Mice. J. Immunol 176: 6254-6261 (2006).

Basu, S., V. R. Jala, S. P. Mathis, S. T. Rajagopal, P. A. Del, P. Maturu, J. O. Trent, and B. Haribabu. 2007. Critical role for polar residues in coupling leukotriene B4 binding to signal transduction in BLT1. Journal of Biological Chemistry 282:10005.

Del Prete. A., W. H. Shao, S. Mitola, G. Santoro, S. Sozzani, and B. Haribabu. 2007. Regulation of dendritic cell migration and adaptive immune response by leukotriene B4 receptors: a role for LTB4 in up-regulation of CCR7 expression and function. Blood 109:626.

Mathis S, Jala VR, Lee DM, Haribabu B.  Non-redundant roles for leukotriene B4 receptors BLT1 and BLT2 in mouse models of inflammatory arthritis J. Immunol  185: 3049-3056 (2010).

Spite M, Hellmann J, Tang Y, Mathis SP, Kosuri M, Bhatnagar A, Jala VR and Haribabu, B. Deficiency of leukotriene B4 receptor, BLT-1, protects from systemic insulin resistance in diet-induced obesity. J. Immunol. 187:1942-9 (2011)

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.  J Immunol. 191(6):3462-70. doi: 10.4049/jimmunol.1300967 (2013).

Hester CM, Jala VR, Langille MG, Umar S, Greiner KA and Haribabu B. Differences in Fecal Microbiota and Short Chain Fatty Acid Content across Older Adults from Various Racial/Ethnic groups: Assessing Factors Related to Colorectal Cancer Risk World J Gasteroenterology  2015 Mar 7;21(9):2759-69. doi: 10.3748/wjg.v21.i9.2759.

Satpathy SR, JalaVR, Bodduluri SR, Krishnan E, HegdeB, HoyleG, FraigM, LusterAD and HaribabuB. Crystalline silica-induced LTB4 mediated inflammation promotes lung tumor growth. NatureCommun2015 Apr 29;6:7064. doi: 10.1038/ncomms8064.

Chheda ZS, Sharma RK, Jala VR, Luster AD, Haribabu B. Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors. J Immunol. 2016 Jul 27. pii: 1502376. [Epub ahead of print] PMID: 27465528