Penn Veterinary Medicine | University of Pennsylvania

Description of Research Expertise

Research Interests
- Molecular control of infective larval development in parasitic nematodes.
- Sensory and neuronal regulation of the infective process in parasitic nematodes.
- Molecular signaling between parasites and their hosts.
- Seasonality of filarial transmission and anti-filarial chemotherapy.

Key words: Strongyloides, Caenorhabditis, Dirofilaria, transcription factor, dauer, G protein, TGF beta, parasite, nematode.

Description of Research
The Lok lab's primary interest is the endogenous mechanism governing developmental arrest and lifespan in parasitic nematodes. In the free-living nematode Caenorhabditis elegans, output from an insulin/IGF-like signal transduction pathway is critical to both these factors. We are currently using the intestinal parasite Strongyloides stercoralis to test the hypothesis that insulin signaling also regulates arrest and reactivation of infective, autoinfective and hypobiotic third-stage larvae, as well as lifespan in these chronic latent stages of parasitic nematodes. In beginning to test this hypothesis we have determined that genes encoding key elements of the C. elegans insulin/IGF pathway are conserved in S. stercoralis. We are now using C. elegans as a genetic surrogate to assess function of Strongyloides ilrk-1 and fktf-1, orthologs of the insulin receptor and forkhead transcription factor, respectively in the C. elegans insulin pathway. Specifically we are asking whether these genes can complement loss-of-function mutations in their orthologs when expressed in C. elegans as heterologous transgenes. In addition to our work with insulin-like signaling, we have also determined that elements of two other signal transduction pathways that regulate dauer development in C. elegans, a G protein-mediated odorant receptor pathway and a TGF-ß-like signal pathway, are also conserved in S. stercoralis. In addition to our work on the molecular and developmental biology of S. stercoralis, we maintain an interest in the biology of Dirofilaria immitis and in clinical management of canine and feline heartworm disease.

Rotation Projects for 2009-2010
1. Mobilizing transposable elements in the genome of Strongyloides stercoralis

2. Mechanisms of transgene inheritance and silencing in Strongyloides stercoralis

3. Structure and function of an insulin/IGF-associated PI3 kinase in Strongyloides stercoralis.

4. Structure and function of a TGF-beta superfamily growth factor in Strongyloides stercoralis.

Lab personnel:
• Holman Massey, Jr., Ph.D. – Research Specialist
• Xinshe Li, Ph.D. – Research Specialist
. Hongguang Shao - Research Specialist
. Najju Ranjit - Postdoctoral Fellow
. He Zhu - Postdoctoral Fellow
. Euihye Jung - Technician
. Angela Halstead - Technician
. James Won - Technician

Selected Publications

Hu, M, LOK, JB, Ranjit, N, Massey, HC Jr., Sternberg, PW, Gasser, RB: Structural and functional characterization of the fork head transcription factor-encoding gene, Hc-daf-16, from the parasitic nematode Haemonchus contortus (Strongylida). Int. J. Parasitol. In Press 2009.

Stein, LH, Redding, KM, Lee, JJ, Nolan, TJ, Schad, GA, LOK, JB3 and Abraham, D.: Eosinophils utilize multiple chemokine receptors for chemotaxis to the parasitic nematode Strongyloides stercoralis J. Innate Immun. In Press 2009.

Wang Z, Zhou XE, Motola DL, Gao X, Suino-Powell K, Conneely A, Ogata C, Sharma KK, Auchus RJ, Lok JB, Hawdon JM, Kliewer SA, Xu HE, Mangelsdorf DJ: Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes. Proc Natl Acad Sci U S A 106: 9138-9143, 2009.

Castelletto M, Massey HC, Jr., LOK JB. (2009) : Morphogenesis of Strongyloides stercoralis infective larvae requires the DAF-16 ortholog FKTF-1. PLoS Pathogens 5(e1000370) 2009.

Junio, AJ, Li, X, Massey, HC Jr., Nolan, TJ, Lamitina, ST, Sundaram, MV and LOK, JB: Strongyloides stercoralis: cell- and tissue-specific transgene expression and co-transformation with vector constructs incorporating a common multifunctional 3’ UTR. Exp. Parasitol. 118: 253-265., 2008.

Ashton, F.T, Zhu, X., Boston, R., Lok, J.B., Schad, G.A. : Strongyloides stercoralis: amphidial neuron pair ASJ triggers significant resumption of development by infective larvae of under host-mimicking in vitro conditions. Exp. Parasitol. 115: 92-97, 2007.

Li X, Massey HC, Nolan TJ, Schad GA, Kraus K, Sundaram M, Lok JB: Successful transgenesis of the parasitic nematode Strongyloides stercoralis requires endogenous non-coding control elements International Journal for Parasitology 36: 671-679, 2006.

Massey HC, Bhopale MK, Li X, Castelletto M, Lok JB.: The fork head transcription factor FKTF-1b from Strongyloides stercoralis restores DAF-16 developmental function to mutant Caenorhabditis elegans International Journal for Parasitology 36: 347-352, 2006.

Massey HC, Jr, Castelletto ML, Bhopale VM, Schad G A, Lok JB: Sst-tgh-1 from Strongyloides stercoralis encodes a proposed ortholog of daf-7 in Caenorhabditis elegans Molecular and Biochemical Parasitology 142: 116-120, 2005.

Massey HC, Jr., Nishi M, Chaudhary K, Pakpour N, Lok JB: Structure and developmental expression of Strongyloides stercoralis fktf-1, an ortholog of daf-16 in Caenorhabditis elegans, a gene encoding a forkhead transcription factor necessary for dauer arrest International Journal for Parasitology 33: 1537-1544, 2003.