Leonard Shultz, Ph.D. - Investigator Profile
Complex biological processes often require in vivo analysis. Our lab has focused on the molecular and cellular basis for spontaneous mutations that disrupt the development or regulation of the hematopoietic and immune systems. We have applied the knowledge gained in these studies to investigations of type 1 diabetes (T1D). The study of human diabetes in vivo is severely limited by ethical and technical constraints. There is a growing need for animal models to carry out in vivo studies on human autoimmune systems to investigate the etiology and pathogenesis of human T1D and to investigate new therapeutic interventions without putting individuals at risk. We have developed humanized mice, or mouse–human chimeras, to overcome these limitations. This research focuses on the development, optimization and validation of humanized mouse models that support engraftment with human hematopoietic cell populations and with human islets. These studies began in 1988 with our report of the SCID-hu mouse model. Over the ensuing two decades we have improved humanized mouse strains, and have optimized the technologies used for stem cells engraftment. Our recent research has leveraged these mouse models for translational studies on human hematopoiesis, immunity, diabetes, regenerative medicine, transplantation tolerance and cancer. We have developed the NOD/SCID mouse strain harboring a null mutation of the IL2 cytokine receptor common g chain and have shown that these mice, referred to as NOD/SCID/Gamma (NSG) mice, can efficiently support development of functional lymphoid and myeloid cells following human hematopoietic stem cell (HSC) engraftment. Development of NSG mice that are ‘humanized’ by engraftment of human tissues, HSCs, and peripheral blood mononuclear cells (PBMCs) has provided an opportunity to study human biological processes in vivo that would otherwise not be possible. The new generations of humanized mice expressing human HLA and cytokine transgenes and carrying additional targeted mutations that further depress host innate immunity are powerful tools in the investigation of T1D as well as other human diseases.
Humanized mouse model for studying diabetes, bone development, autoimmunity