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Primary Research Focus
The research in the Savinov laboratory is focused on studying the underlying mechanisms controlling organ-specific autoimmune diseases such as type I diabetes (T1D). Progression of T1D involves the activation of autoimmune T cells, consequent homing of activated lymphocytes to the pancreatic islets, and ensuing destruction of insulin-producing beta cells. By determining how autoimmune T cells are initially activated during T1D pathogenesis, how they home to the target organ and how they destroy their beta cell targets, causing clinical onset of T1D, we hope to find an effective molecular therapy capable of controlling the autoimmune process.
Behind the research
Pathogenesis of autoimmune diseases is extremely complex. Specifically, T1D pathogenesis is characterized with continuous destruction of insulin-producing β-cells within the pancreatic islets by autoreactive islet-specific T lymphocytes. Savinov’s lab current research projects are focused on the mechanisms involved in the regulation of T-cell activation and tolerance in regard to T1D, even though most of them could take place in other autoimmune processes. Using genetic mouse models, and variety of primary and established cell lines, we are examining the molecular mechanisms leading to inefficient negative co-stimulation, a control mechanism for T cell activation by auto-antigens, along with some defects in the intracellular signaling cascades involved in the autoimmune process. Multiple cellular, biochemical and animal-related experimental techniques are utilized by the laboratory such as, cloning, expression and purification of recombinant proteins, generation of stable cell lines, isolation of variety of primary cell types, immunohistochemistry, drug-treatment of animals, adoptive transfer and a range of immunological assays.
We have multiple previous and currently ongoing projects and collaborations with researchers from Sanford Research, USD, DiaMedica Therapeutics (Minneapolis, MN), Compugen (Toronto, Canada) and the University of Florida, Department of Pathology, Immunology and Laboratory Medicine (Gainesville, FL).
- Studying biochemical and immunomodulatory properties of the negative co-stimulatory molecule B7H4, also known as V-set domain-containing T-cell activation inhibitor 1 (VTCN1).
- Designing and applying a therapy for T1D using recombinant, VTCN1-based molecules.
- Studying the immunomodulation by vascular and lymphatic endothelial cells’ subsets expressing negative costimulatory molecules such as V-domain Ig suppressor of T cell activation (VISTA) and Programmed death-ligand 1 (PD-L1).
- Identifying the full spectra of protein interactions of protein tyrosine phosphatase nonreceptor type 22 (PTPN22) and the differences in these interactions between its two variants – PTPN22-R and PTPN22-W. PTPN22 promotes intracellular signaling downstream of TCR, BCR, TLRs and IFNGR1 in lymphoid and myeloid cells. These two variants have only one amino acid difference at position 620. R620W variant is a major susceptibility risk factor for autoimmunity and the careful dissection of all interactions that PTPN22 is involved in could be crucial for finding novel targets for autoimmunity treatment.
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