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:
Alexander, G. M., Erwin, K. L., Byers, N., Deitch, J. S., Augelli, B. J., Blankenhorn, E. P., and T. D. Heiman-Patterson. Effect of transgene copy number on survival in the G93A SOD1 transgenic mouse model of ALS. Brain Res. Mol. Brain Res., 130: 7-15, 2004.
Heiman-Patterson, T. D., Deitch, J. S., Blankenhorn, E. P., Erwin, K. L., Perreault, M. J., Alexander, B. K., Byers, N., Toman, I., and G. M. Alexander. Background and gender effects on survival in the TgN(SOD1-G93A)1Gur mouse model of ALS. J. Neurol. Sci., 236: 1-7, 2005.
Blankenhorn, E. P., Rodemich, L., Martin-Fernandez, C., Leif, J., Greiner, D. L., and J. P. Mordes. The rat diabetes susceptibility locus Iddm4 and at least one additional gene are required for autoimmune diabetes induced by viral infection. Diabetes, 54: 1233-1237, 2005.
Teuscher, C., Doerge, R. W., Fillmore, P. D., and E.P. Blankenhorn. eae36, a locus on mouse chromosome 4, controls susceptibility to experimental allergic encephalomyelitis in older mice and mice immunized in the winter. Genetics, 172(2): 1147-1153, 2006.
Teuscher, C., Noubade, R., Spach, K., McElvany, B., Bunn, J. Y., Fillmore, P. D., Zachary, J. F., and E. P. Blankenhorn. Evidence that the Y chromosome influences autoimmune disease in male and female mice. Proc. Natl. Acad. Sci. U S A, 103(21): 8024-8029, 2006.
Cunningham, T. J., Yao, L., Oetinger, M., Cort, L., Blankenhorn, E. P., and J. I. Greenstein. Secreted phospholipase A2 activity in experimental autoimmune encephalomyelitis and multiple sclerosis. J. Neuroinflammation, 3(1): 26, 2006.
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.
Wallis, R. H., Wang, K., Dabrowski, D., Marandi, L., Ning, T., Hsieh, E., Paterson, A. D., Mordes, J. P., Blankenhorn, E. P., and P. Poussier. A novel susceptibility locus on rat chromosome 8 affects spontaneous but not experimentally induced type 1 diabetes. Diabetes, 56(6): 1731-1736, 2007.
Blankenhorn, E. P., Descipio, C., Rodemich, L., Cort, L., Leif, J. H., Greiner, D. L., Mordes J. P. Refinement of the Iddm4 diabetes susceptibility locus reveals TCRVbeta4 as a candidate gene. Ann. N. Y. Acad. Sci., 1103: 128-131, 2007.
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.
Noubade, R., Saligrama, N., Spach, K., Del Rio, R., Blankenhorn, E. P., Kantidakis, T., Milligan, G., Rincon, M., and C. Teuscher. Autoimmune disease-associated histamine receptor H1 alleles exhibit differential protein trafficking and cell surface expression. J. Immunol. 180(11): 7471-7479, 2008. Erratum in: J. Immunol., 181(7): 5174, 2008.
Lu, C., Pelech, S., Zhang, H., Bond, J., Spach, K., Noubade, R., Blankenhorn, E. P., and C. Teuscher. Pertussis toxin induces angiogenesis in brain microvascular endothelial cells. J. Neurosci. Res., 86(12): 2624-2640, 2008.
Noubade, R., del Rio, R., McElvany, B., Zachary, J. F., Millward, J. M., Wagner, D. D., Offner, H., Blankenhorn, E. P., and C. Teuscher. von-Willebrand factor influences blood brain barrier permeability and brain inflammation in experimental allergic encephalomyelitis. Am. J. Pathol., 173(3): 892-900, 2008.
Spach, K. M., Blake, M., Bunn, J. Y., McElvany, B., Noubade, R., Blankenhorn, E. P., and C. Teuscher. Cutting edge: the Y chromosome controls the age-dependent experimental allergic encephalomyelitis sexual dimorphism in SJL/J mice. J. Immunol., 182(4): 1789-1793, 2009.
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, Feb 10, 2009, Epub ahead of print.
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