Herbert B. Tanowitz, M.D.
This laboratory investigates the pathogenesis of chagasic heart disease, caused by the parasite Trypanosoma cruzi. Chagas’ disease is also an opportunistic infection in HIV/AIDS. We are examining signaling pathways involved in cardiac remodeling as a consequence of the T. cruzi infection. This laboratory is examining the consequences of this infection on cell cycle regulatory proteins (i.e., cyclins) in vitro. Previously, we found that infection induces ERK activation and modulation of the expression and/or activity of cyclins, which function as mediators of cellular proliferation and differentiation. Cyclins are also responsible for remodeling in the cardiovascular system. Therefore, the kinetics of the expression of cyclins in infected cultured cells and co-culture systems are to be studied. In addition, in the mouse model of Chagas' disease the kinetics of expression of cell cycle regulatory proteins in the cells of the myocardium of infected mice will be determined and correlated with progression of cardiomyopathy. The mechanisms underlying the alterations in these proteins in the myocardium will be investigated. The contribution of cyclin D1 in cardiovascular remodeling will be investigated utilizing mouse models including cyclin D1 KO mice and mice in which ET-1 has been selectively deleted from cardiac myocytes.
The relationship between obesity and infectious diseases has become an important issue. The role of glucose metabolism and the role of the fat cell in the pathogenesis of both acute and chronic Chagas' disease have never been fully explored. We have demonstrated that T. cruzi invades cultured fat cells and in addition invades and persists in adipose tissue where it upregulates inflammatory mediators. Moreover, infection alters glucose metabolism and adiponectin levels. Together with the Scherer lab (Cell Biology) we plan to utilize a novel mouse model of inducible lipoatrophy that has been developed to determine the precise temporal involvement of adipocytes during both the acute and the chronic stages of Chagas’ disease. In these mice we will characterize the metabolic alterations using the euglycemic clamp procedure. The adipocyte-derived factor adiponectin has been widely implicated in the pathogenesis of heart disease. Using a novel model of adiponectin null mice, the role of adiponectin in cardiac hypertrophy will be evaluated in infected mice. It is expected that these studies will contribute significantly towards a better understanding of Chagas' disease development in dysregulated metabolic states such as HIV lipodystrophic patients, associated with decreased insulin sensitivity and decreased circulating levels of adiponectin.
As an outgrowth of their interest in ET-1 we have investigated its role in the pathogenesis of cerebral malaria. Recently, we reported that in cerebral malaria in mice there is a reduction in blood flow and an increased expression of ET-1 in this mouse model. Further studies will evaluate the role of ET-1 in this process.
- Nagajyothi FNU, Zhao D, Machado FS, Weiss LM, Schwartz GJ, Desruisseaux MS, Zhao Y, Factor SM, Huang H, Albanese C, Teixeira MM, Scherer PE, Chua SC Jr, Tanowitz HB. Crucial role of the central leptin receptor in murine Trypanosoma cruzi infection. J Inf Dis 202:1104-13, 2010.
- Mukherjee S, Machado FS, Huang H, Oz HS, Jelicks LA, Prado CM, Koba W, Fine EJ, Zhao D, Factor SM, Collado JE, Weiss LM, Tanowitz HB, Ashton AW. Aspirin treatment of mice infected with Trypanosoma cruzi and implications for the pathogenesis of Chagas disease. PLoS One. 15;6(2):e16959, 2011.
- Matos Ferreira AV, Segatto M, Menezes Z, Macedo AM, Gelape C, de Oliveira Andrade L, Nagajyothi F, Scherer PE, Teixeira MM, Tanowitz HB. Evidence for Trypanosoma cruzi in adipose tissue in human chronic Chagas disease. Microbes Infect. 13:1002-1005, 2011.
- Nagajyothi F, Machado FS, Burleigh BA, Jelicks LA, Scherer PE, Mukherjee S, Lisanti MP, Weiss LM, Garg NJ, Tanowitz HB. Mechanisms of Trypanosoma cruzi persistence in Chagas disease. Cell Microbiol. 14:634-643, 2012.
- Mukherjee S, Sadekar N, Ashton AW, Huang H, Spray DC, Lisanti MP, Machado FS, Weiss LM, Tanowitz HB. Identification of a functional prostanoid-like receptor in the protozoan parasite, Trypanosoma cruzi. Parasitol Res 112:1417-25 , 2013.
- Nagajyothi F, Weiss LM, Zhao D, Koba W, Jelicks LA, Cui MH, Factor SM, Scherer PE, Tanowitz HB. High Fat Diet Modulates Trypanosoma cruzi Infection Associated Myocarditis. PLoS Negl Trop Dis. 2014 Oct 2;8(10):e3118.
- Tanowitz H, Machado FS. Other helminthic infections: Ascariasis, Dracontiasis, Lagochilascariasis, Micronemiasis. Handbook of Clinical Neurology, volume 114, chapter 21, pages 263–268. 2013.
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