Ph.D. Molecular Biology
1997, University of Georgia
Research Focus Areas
Molecular and Biochemical Parasitology
Surface Molecule Expression
My laboratory is interested in the study of host-parasite interactions with a focus on the molecular mechanisms by which parasitic organisms monitor and respond to their environments. Our model organism is the protozoan parasite Trypanosoma brucei that inhabits two distinct biological niches – the tsetse fly vector and the mammalian bloodstream. Moving between these two environments requires modulation of a number of biological processes and pathways in a coordinated and tightly regulated fashion.
During its lifecycle, T. brucei uses fluctuating glucose levels as one signal to “sense” its environment. For a small molecule to serve as an effective “marker” for a particular environment, its availability must change from one niche to another. Glucose is an example of such a molecule. Short stumpy form parasites ingested by a feeding tsetse fly experience a rapid drop in glucose concentration, with the sugar in the blood nearly depleted in ~15 minutes. Bloodstream form (BSF) parasites that infect mammals also encounter changes in glucose concentrations. Both cerebrospinal fluid and blood glucose concentrations increase in febrile children (fever is frequently associated with trypanosomiasis), while mice infected with T. rhodesiense have decreased serum glucose.
Regulation of TbHKs
In general, there are multiple processes that can be used to regulate genes and their products. Alteration of gene expression through modulation in the rates of transcription, turn-over of steady-state RNA, and/or translation can influence the types of pathways available for catabolic/anabolic metabolism. Additionally, enzyme activity can be regulated by a number of mechanisms, including localization, multimerization, allosteric regulation, and a spectrum of post-translational modifications such as phosphorylation and glycosylation. Our long-term goal is to identify and characterize pathways that the parasite uses to modulate metabolic and developmental regulation in response to environmental changes within the host, with a particular focus on dissecting the role of trypanosome hexokinases (TbHKs) in these responses. We hypothesize that TbHK activity responds to, and is regulated by, cues provided by the host. Additionally, TbHKs likely serve a central regulatory role in the glucose response pathway. These hypotheses have been developed based on our efforts, both published and preliminary. Understanding the regulation and function of these essential proteins will provide new approaches for much-needed development of therapeutics for this parasite and could provide insight into glucose sensing in a variety of other systems, including higher eukaryotes.
Developmental and environmental regulation of TbHK gene expression
One area of emphasis in my group has been the resolution of cellular mechanisms involved in regulation of both transcript abundance and expression in response to environmental cues. For example, we have found that the differential polyadenylation of TbHK1 transcripts reported by Siegel et al (7 total mature mRNAs were identified by RNASeq) yields products that are maintained and expressed at different levels depending on environmental conditions. This process may involve differential polyadenylation in response to environmental cues, or preferential maintenance of particular species of transcripts depending on growth conditions.
Mechanisms for dynamic modulation of TbHK enzyme activity
One of our over-arching goals is to identify and characterize pathways that T. brucei uses to modulate metabolic and developmental regulation. We have made significant contributions to identifying potential metabolic regulators of TbHK activity within the cell, including the finding that free fatty acids can modulate enzyme activity in vitr. Further, free fatty acids can dissociate TbHK hexamers, suggesting that regulated disassembly and reassembly could be a cellular mechanism for regulation of enzyme activity. We continue to explore enzyme activity regulation with respect to multimerization and interaction with cellular metabolites.
Development of TbHK1 inhibitors as lead compounds for therapeutic development
The observation that T. brucei HKs have unique properties and are situated at the crossroads of important metabolic pathways suggests that these enzymes may be attractive drug targets. Indeed, inhibitors of trypanosome HK activity have been found to be trypanocidal to parasites grown in culture, albeit at high concentrations , and we have genetic evidence that TbHKs are essential.
To identify new TbHK1 inhibitors, we developed a collaboration with the University of Pittsburgh Drug Discovery Institute (DDI) to screen their small molecule library (~ 223,000 compounds) for inhibitors of recombinant TbHK1. In addition to TbHK1 inhibition, compounds were tested against Leishmania promastigoes, human cells, and BSF T. brucei. This campaign yielded promising leads, which are now in analog development through collaboration with the Kansas University Specialty Chemistry Center. We look forward to continued structure-activity relationship analysis, as well as testing promising leads against the African trypanosome in both acute and chronic infection animal models.
Long term objectives
Our research continues to provide insight into the regulation and function of two highly related HKs from the important pathogen T. brucei. These findings have also extended our understanding of mechanisms that the parasite uses to monitor its environment.The digenic lifestyle of the parasite requires dramatic developmental changes in response to marked differences in environment. Failure to regulate development in response to the environment (for example, inappropriate PF surface molecule expression in the BSF parasite) would likely be catastrophic for the parasite. One could envision a number of signaling pathways converging in response to the change of hosts from fly to mammal and back again, and we look forward to dissecting out the role of nutrient sensing in this complicated cascade.
National Institutes of Health
Nutrient Sensing and Hexokinases in T. brucei
National Institutes of Health
Tuning of cellular efficacy and profiling of cross-species antiparasitic potential by additional SAR rounds by synthesis of Trypanosoma brucei hexokinase 1 inhibitors
2005, 2008, 2009, 2011 Nominee, College of AFLS Teacher of the Year
2005 Clemson University National Scholars Program Award of Distinction for Teaching
2004 Elected Full Member of Sigma Xi
Introduction to Genetics
Introduction to Genetics Laboratory
Biochemical Basis of Disease
Proteomics and Genomics
Joice, AC, Harris, MT, Kahney, EK, Dodson, HC, Maselli, AG, Whitehead, DC, and Morris JC. Exploring the mode of action of ebselen in Trypanosoma brucei hexokinase inhibition. (2013) The International Journal for Parasitology: Drugs and Drug Resistance 3, 154-160. (*Selected as “Editor’s Choice”)
Harris, MT, Mitchell, WG, Morris, JC. Targeting protozoan parasite metabolism: glycolytic enzymes in the therapeutic crosshairs. (In Press) Current Medicinal Chemistry.
Bauer, ST, Morris, JC, Morris, MT. Environmentally-regulated glycosome protein composition in the African trypanosome. (2013) Eukaryotic Cell 12, 1072-1079.
Harris, MT, Walker, DM, Drew, ME, Mitchell, WG, Dao, K, Schroeder, CE, Flaherty, DP, Weiner, WS, Golden JE, and Morris, JC. Interrogating a Hexokinase-Selected Small Molecule Library for Inhibitors of Plasmodium falciparum Hexokinase. (2013) Antimicrobial Agents and Chemotherapy 57, 3731-3737.
Lin, S, Morris, MT, Ackroyd, CP, Morris, JC, Christensen, KA. Peptide targeted delivery of pH sensor for quantitative measurements of intraglycosomal pH in live Trypanosoma brucei. (2013) Biochemistry 52, 3629-3637.
Joice, AC, Lyda, TL, Sayce, AC, Verplaetse, E, Morris, MT, Michels, PAM, Robinson, DR, Morris, JC. Extra-glycosomal localization of Trypanosoma brucei Hexokinase 2. (2012) The International Journal for Parasitology 42,401-409. (*Selected as “Editor’s Choice”)
Sharlow E, Golden JE, Dodson H, Morris M, Hesser M, Lyda T, Leimgruber S, Schroeder CE, Flaherty DP, Weiner WS, Simpson D, Lazo JS, Aubé J, Morris JC. Identification of inhibitors of Trypanosoma brucei hexokinases. (2010, updated 2011) Probe Report from the NIH Molecular Libraries Program. National Center for Biotechnology Information.
Dodson, HC, Morris MT, Morris JC. Glycerol-3-phosphate alters Trypanosoma brucei hexokinase activity in response to environmental change. (2011) The Journal of Biological Chemistry 286, 33150-33157.
Coley, A, Dodson, H, Morris, M, Morris JC. Glycolysis in the African Trypanosome: Targeting Enzymes and their Subcellular Compartments for Therapeutic Development. (2011) Molecular Biology International, doi:10.4061/2011/123702.
Hesser, MW, Morris, JC, Gibbons, JR. Advances in recombinant gonadotropin production for use in bovine superovulation. (2011) Reproduction in Domestic Animals , doi: 10.1111/j.1439-0531.2011.01767.x.