Drexel University College of Medicine

The goal of the research in our laboratory is to understand the genetic basis for inherited susceptibility to autoimmune diseases, including diabetes and multiple sclerosis, and the genetic architecture of wound healing. Backcross and F2 progeny are screened for alleles at a large number of genetic loci. The inheritance of these alleles is compared to the inheritance of the phenotype (“linked”) and a preliminary assignment of the location of incidence and quantitative trait loci (QTL) is made. The QTL are confirmed in subsequent crosses, or are fixed in the genome by selective breeding, for the purpose of positional cloning and identification of the disease gene itself.

Left: ANA antibody from a scleroderma mouse model, Right: Skin from a scleroderma mouse model and control

We currently have several projects underway, including studies to examine the genetic control of susceptibility to experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis, in mice. A second project is to map EAE-susceptibility loci in the LEW rat, the prototype strain for this phenotype, and to understand the role of the TCR haplotype in severity of EAE. In recent years, we have applied this method to study susceptibility to retroviral infections and induced lymphomas in mice. We are extending our finding that diabetes in the DP-BB rat is controlled by a QTL we discovered on chromosome 4. This work also involves making a congenic for the chromosome 4 diabetogenic locus to provide material for positional cloning of this QTL. Finally, in collaboration with the Wistar Institute, we are mapping wound healing genes in several large crosses to confirm our original mapping of six QTL associated with the trait of wound healing/regeneration, and to understand the significant sexual dimorphism in the genetic control of this trait.

Mapping a diabetes gene in rats and human cohorts: Ubd is a candidate gene

Selected Publications:

1.  Ma, R.Z., Gao, J., Meeker, N. D., Fillmore, P. D., Tung, K. .S. K., Watanabe, T., Zachary, J. F., Offner, H., Blankenhorn, E. P., and C. Teuscher.  Identification of Bphs, an Autoimmune Disease Locus, as Histamine Receptor H1.  Science, 297: 620-623,  2002
2. Norose, K., Yano, A., Zhang, X. M., Blankenhorn, E., and E. Heber-Katz.  Mapping of genes involved in murine herpes simplex virus keratitis:  Identification of genes and their modifiers.  J. Virol., 76: 3502-3510, 2002.
3. Abiola, O., Angel, J. M., Avner, P., Bachmanov, A. A., Belknap, J. K., Bennett, B., Blankenhorn, E. P. et al.  Complex Trait Consortium.  The nature and identification of quantitative trait loci: a community's view.  Nat. Rev. Genet., 4: 911-916, 2003.
4. Heber-Katz, E, Chen, P., Clark, L., Zhang, X., Troutman, S., and E. P. Blankenhorn.  Regeneration in MRL mice: further genetic loci controlling the ear hole closure trait using MRL and M.m. castaneus mice.  Wound Repair Regen., 12:384-392, 2004.
5. Teuscher, C., Noubade, R., Spach, K., Bunn, J. Y., Fillmore, P. D., Zachary, J. F., and E P. Blankenhorn.  Evidence that the Y-Chromosome influences EAE in male and female mice.  Proc. Natl. Acad. Sci. USA, 103: 8024-8029, 2006.
6. Noubade, R., Milligan, G., Zachary, J. F., Blankenhorn, E. P., del Rio, R., Rincon, M., and C. Teuscher.  Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-gamma production in mice.  J. Clin. Invest., 117(11): 3507-3518, 2007.
7. Teuscher, C., Subramanian, M., Noubade, R., Gao, J. F., Offner, H., Zachary, J. F., and E. P. Blankenhorn.  Central histamine H3 receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS.  Proc. Natl. Acad. Sci. U S A, 104(24): 10146-10151, 2007.
8. Blankenhorn, E. P., Bryan, G., Kossenkov, A. V., Clark, L. D., Zhang, X. M., Chang, C., Horng, W., Pletscher, L. S., Cheverud, J. M., Showe, L. C., and E. Heber-Katz.  Genetic loci that regulate healing and regeneration in LG/J and SM/J mice.  Mamm. Genome, 20: 720-733. 2009.
9. Blankenhorn, E. P., Cort, L., Greiner, D. L., Guberski, D. L., and J. P. Mordes.  Virus-induced autoimmune diabetes in the LEW.1WR1 rat requires Iddm14 and a locus proximal to the major histocompatibility complex.  Diabetes, 58: 2930-2938, 2009.
10. Fuller, J. M., Bogdani, M., Tupling, T. D., Jensen, R. A., Pefley, R., Manavi, S., Cort, L., Blankenhorn, E. P., Mordes, J. P., Lernmark, A., and A. E. Kwitek.  Genetic dissection reveals diabetes loci proximal to the gimap5 lymphopenia gene.  Physiol. Genomics, 10;38(1): 89-97, 2009.
11. Mordes, J. P., Cort, L., Norowski, E., Leif, J., Fuller, J. M., Lernmark, A., Greiner, D. L., and E. P. Blankenhorn.  Analysis of the rat Iddm14 diabetes susceptibility locus in multiple rat strains: identification of a susceptibility haplotype in the Tcrb-V  locus.  Mamm. Genome, 2009 (3): 162-169, 2009.
12. Spach, K. M., Blake, M., Bunn, J. Y., McElvany, B., Noubade, R., Blankenhorn, E. P., an C. Teuscher.  Cutting edge: the Y chromosome controls the age-dependent experimental allergic encephalomyelitis sexual dimorphism in SJL/J mice.  J. Immunol., 182: 1789-1793, 2009.
13. Spach, K. M., Noubade, R., McElvany, B., Hickey, W. F., Blankenhorn, E. P., and C. Teuscher.  A single nucleotide polymorphism in Tyk2 controls susceptibility to experimental allergic encephalomyelitis.  J. Immunol., 182(12): 7776-7783, 2009.
14. Tirabassi, R. S., Guberski, D. L., Blankenhorn, E. P., Leif, J. H., Woda, B. A., Liu, Z., Winans, D., Greiner, D. L., and J. P. Mordes.  Infection with viruses from several families triggers autoimmune diabetes in LEW.1WR1 rats: prevention of diabetes by maternal immunization.  Diabetes, 59(1): 110-118, 2009.
15. Case, L. K., Del Rio, R., Bonney, E. A., Zachary, J. F., Blankenhorn, E. P., Tung, K. S., and C. Teuscher.  The postnatal maternal environment affects autoimmune disease susceptibility in A/J mice.  Cell. Immunol., 260(2): 119-127, 2010.