Functional Genomics of Type 1 Diabetes

Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing islet cells and afflicts 0.3-0.6 percent of North Americans. The disease is multifactorial caused by genetic variation at multiple loci, modified by poorly defined environmental factors. The objective of our research program is to 1) identify genes that control this process in mouse models and in human patients, 2) understand the autoimmune response that results in islet cell death, and 3) to test the idea that early immune system exposures to microbes significantly modifies genetic risk for developing T1D. We use positional cloning, gene expression microarray analysis and immunological analyses to identify the pathways controlled by T1D risk genes and understand how they are modified by exposure to intestinal commensal bacteria. We are also engaged in high-throughput human gene association studies of T1D.

Molecular pathways of Acute Lymphoblastic Leukemia
Our research program is designed to probe the developmental steps and mechanisms of leukemia in mouse models and in human patients. The objective of this program is to translate knowledge gained in mouse models and primary human leukemia, to improve the diagnosis and treatment of leukemia. Our specific areas of interest are: 1) signalling pathways that govern cell survival, differentiation or death fate decisions in normal and neoplastic lymphoid cells, 2) identification and analysis of the cells that initiate and sustain the leukemic clone (cancer stem cells) to understand molecular pathways underlying leukemia initiation and progression, and 3) how leukemic blasts expand in the central nervous system (CNS) causing a major clinical complication of leukemia and lymphomas, and 4) features of the immune system that determine engraftment of normal human blood stem cells in settings of clinical transplantation.

Link to Dr. Danska's laboratory website: http://www.sickkids.ca/danskalab

Graduate Students:

• Eniko Papp
• Tatiana Perova
• Peggy Wong

Selected References: (*authors include Univ. of Toronto graduate)

• Ivakine EA, Gulban O, Mortin-Toth SM, Scott C, Surrell D, Canty A, Danska JS. (2006). Molecular genetic analysis of the Idd4 locus implicates the interferon response in Type 1 diabetes in susceptibility of NOD mice. J. Immunol. 176 :2976-90.

• Matei IR, Gladdy RA, Nutter L, Guidos CJ, Danska JS (2007) ATM deficiency disrupts Tcra locus integrity and the maturation of CD4+CD8+ thymocytes. Blood 109 :1887-96.

• Takenaka K, Prasolava TK, Wang JC, Mortin-Toth SM, Khalouei S, Gan OI, Dick JE, Danska JS. (2007) Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat. Immunol. 8: 1313-1323. See also News and Views 8: 1287-1289.