Biomedical Research Education & Training
Faculty Member

Hill, George C., Ph.D.
Professor of Medical Education and Administration Emeritus
Professor of Pathology, Microbiology and Immunology Emeritus

Lab Url: N/A

Phone Number: 615-322-7498

Email Address: George.Hill@vanderbilt.edu

Hill, George's picture
Academic history
B.S., Rutgers University, Camden, NJ
M.S., Howard University, Washington, D.C.
Ph.D., New York University, New York City, NY
, University of Kentucky Medical Center, Lexington, KY
, Molteno Institute, University of Cambridge, Cambridge, Great Britain

Office Address   Mailing Address

301 Light Hall 0190


Research Keywords
African trypanosomes,mitochondrial biogenesis,trypanosome alternative oxidase (TAO),developmentally-regulated genes,RNA interference,trypanocidal drug development,Biochemistry,Infectious disease,Microbiology

Clinical Research Keywords
Health disparities in minority populations.

Research Specialty
Molecular and biochemical basis of differentiation and characterization of the trypanosome alternative oxidase in African trypanosomes, the causative agent of African trypanosomiasis.

Research Description
Trypanosoma brucei is the causative agent of African trypanosomiasis and is a re-emerging infection in sub-Sahara Africa. In both the bloodstream and insect vector stages, there is a unique cyanide insensitive, salicylhydroxamic acid (SHAM) sensitive alternative oxidase that is expressed. This trypanosome alternative oxidase (TAO) is the only oxidase present in the bloodstream forms. However, in addition to the TAO, the procyclic trypanosomes contain an established cytochrome system. Our laboratory has characterized the electron transport systems in both systems.

We have identified the TAO as a potential target for trypanocidal drugs and begun to synthesize compounds that inhibit the TAO in vitro and in vivo. In the bloodstream stages, this unique cyanide insensitive, salicylhydroxamic acid (SHAM) sensitive alternative oxidase is expressed as the only oxidase present in the bloodstream forms. RNA interference (RNAi) studies have been performed that demonstrate that the TAO is essential for survival. RNAi plasmid constructs using p2T7ti_B/GFP were made, linearized and transfected into T. brucei 427 bloodstream trypomastigotes. After transfection, selection, and induction, the TAO message in bloodstream transfectants was markedly reduced in the presence of tetracycline after 48 hours. Importantly, immunoblot analysis revealed that there was also approximately a 1.5 fold decrease in the TAO protein level in these bloodstream cells after RNAi induction. In vivo studies revealed that there was a five-fold reduction in the parasitemia levels in RNAi induced mice and rats infected with T. brucei RNAi-transfected cells and their life was extended, clearly demonstrating the proof of principal that the TAO can serve as an effective target for trypanocidal drugs. There was also a five-fold reduction in the TAO protein level isolated from parasites infected in RNAi induced mice as compared to the control. Additionally, respiration assays of RNAi-transfected T. brucei isolated from rats revealed that there was 100% SHAM inhibition in cells induced with tetracycline.

The prenylated salicylic acid derived substructural motif is the key chemical and/or structural feature important for inhibition of TAO within the limited series of exploratory compounds we have investigated. It has also been demonstrated that synthesizing carbohydrate-linked analogs improves solubility properties. Further testing of compounds in this category is being pursued as well as studies testing the effectiveness of these compounds in laboratory models of trypanosomiasis.

Current efforts are also being devoted to the purification of the TAO and subsequent crystallization of this essential enzyme in African trypanosomes, the causative agent of African sleeping sickness.

Major Collaborators:

Minu Chaudhuri, Ph.D. - Meharry Medical College, Department of Microbiology, Nashville, TN
Kelly Chibale, Ph.D. - University of Cape Town, Department of Chemistry, Cape Town, South Africa

Publications
Lepesheva, GI, Ott, RD, Hargrove, TY, Kleshchenko, YY, Schuster, I, Nes, WD, Hill, GC, Villalta, F, Waterman, MR. Sterol 14alpha-demethylase as a potential target for antitrypanosomal therapy: enzyme inhibition and parasite cell growth. Chem Biol, 14(11), 1283-93, 2007 PMCID:2324070

Lepesheva, GI, Zaitseva, NG, Nes, WD, Zhou, W, Arase, M, Liu, J, Hill, GC, Waterman, MR. CYP51 from Trypanosoma cruzi: a phyla-specific residue in the B'' helix defines substrate preferences of sterol 14alpha-demethylase. J Biol Chem, 281(6), 3577-85, 2006 PMCID:2324070

Ott, R, Chibale, K, Anderson, S, Chipeleme, A, Chaudhuri, M, Guerrah, A, Colowick, N, Hill, GC. Novel inhibitors of the trypanosome alternative oxidase inhibit Trypanosoma brucei brucei growth and respiration. Acta Trop, 100(3), 172-84, 2006 PMCID:2324070

Walker, Robert, Saha, Lipi, Hill, George C, Chaudhuri, Minu. The effect of over-expression of the alternative oxidase in the procyclic forms of Trypanosoma brucei. Mol Biochem Parasitol, 139(2), 153-62, 2005

Lepesheva, Galina I, Nes, W David, Zhou, Wenxu, Hill, George C, Waterman, Michael R. CYP51 from Trypanosoma brucei is obtusifoliol-specific. Biochemistry, 43(33), 10789-99, 2004

Ajayi, Wilfred U, Chaudhuri, Minu, Hill, George C. Site-directed mutagenesis reveals the essentiality of the conserved residues in the putative diiron active site of the trypanosome alternative oxidase. J Biol Chem, 277(10), 8187-93, 2002

Chaudhuri, Minu, Sharan, Rita, Hill, George C. Trypanosome alternative oxidase is regulated post-transcriptionally at the level of RNA stability. J Eukaryot Microbiol, 49(4), 263-9, 2002

Chaudhuri, M, Ajayi, W, Hill, G C. Biochemical and molecular properties of the Trypanosoma brucei alternative oxidase. Mol Biochem Parasitol, 95(1), 53-68, 1998

Chaudhuri, M, Hill, G C. Cloning, sequencing, and functional activity of the Trypanosoma brucei brucei alternative oxidase. Mol Biochem Parasitol, 83(1), 125-9, 1996

Chaudhuri, M, Ajayi, W, Temple, S, Hill, G C. Identification and partial purification of a stage-specific 33 kDa mitochondrial protein as the alternative oxidase of the Trypanosoma brucei brucei bloodstream trypomastigotes. J Eukaryot Microbiol, 42(5), 467-72, 1995

Wirtz, E, Sylvester, D, Hill, G C. Characterization of a novel developmentally regulated gene from Trypanosoma brucei encoding a potential phosphoprotein. Mol Biochem Parasitol, 47(1), 119-28, 1991

Bass, H S, Njogu, R M, Hill, G C. Solubilization and partial purification of glycerol-3-phosphate oxidase from mitochondria of Trypanosoma brucei. Exp Parasitol, 70(4), 486-9, 1990

Bass, H. S. and Hill, G. C. Approaches to the solubilization and partial purification of glycerol-l-3- phosphate oxidase from mitochondria from trypanosomes. Zoological Science , 7, 35-42, 1990

Sylvester, D A, Hill, G C. A comparison of the amino acid sequences of Crithidia fasciculata and Trypanosoma rhodesiense cytochromes c. J Parasitol, 76(3), 445-7, 1990

Hill, G. C. Benavides, G., Chaudhuri, S. and Sylvester, D. Expression of mitochondrial and nuclear genes during differentiation of African trypanosomes. Molecular Strategies of Parasitic Invasion (ed. Agabian. N. Goodman H. and Noguiera: NY) Anal Liss, Inc., New York, NY, 1987

LeFebvre, R. B. and Hill, G. C. The effects of Trypanosoma brucei differentiating bloodstream trypomastigotes and established procyclic trypomastigotes when grown in the presence of respiratory inhibitors. J. Parasitol, 72, 481-483, 1986

LeFebvre, R. B. and Hill, G. C. Trypanosoma brucei rhodesiense: Mitochondrial proteins of bloodstream and procyclic trypomastigotes. Exper Parasitol., 62, 85-91, 1986

Tielens, A. G. M. and Hill, G. C. The solubilization of a SHAM sensitive, cyanide insensitive ubiquinol oxidase from Trypanosoma brucei. J. Parasitol., 71, 384-386, 1985

Johnson, B. J. B., Hill, G. C., and Donelson, J. E. The maxicircle of Trypanosoma brucei kinetoplast DNA encodes apocytochome c. Mol. Biochem. Parasitol. , 13, 135-146, 1984

Bienen, E. J., Hill, G. C. and Shin, K. Elaboration of mitochondrial function during Trypanosoma brucei differentiation. Mol. Biochem. Parasitol., 7, 75-86, 1983

Folkers, K. Vadhanavikit, S., Bueding, E., Hill, G. and Whittaker, C. Identification of forms of coenzymes Q in organisms including some causing tropical diseases. Chemiker. Zatung, 07, 131-133, 1983

Njogu, R. M. Whittaker C. and Hill, G. C. Evidence for a branched electron transport chain Trypanosoma brucei. Biochem. Parasitol., 1, 13-39, 1980

Hill, G. C., Shimer, S., B. Caughey and Sauer. Growth of infective forms of Trypanosoma rhodesiense in vitro, the causative agent of African trypanosomiasis. Science, 202, 763-765, 1978

Hill, G. C. Electron transport systems in Kinetoplastida. Biochem. Biophys. Acta , 456, 149-193, 1976


Postdoctoral Position Available
No

Postdoctoral Position Details
N/A

Updated Date
12/19/2011