Most patients and particularly women with type-2 diabetes mellitus develop cardiovascular disease with substantial loss of life expectancy. Nonfatal cardiovascular disease contributes greatly to healthcare costs and decreased quality of life in patients with diabetes. Atherogenic dyslipidemia, also called diabetic dyslipidemia, describes the lipid abnormalities in people with insulin resistance, metabolic syndrome, and type-2 diabetes and is one of the strongest and independent predictors for cardiovascular disease. Recent efforts to reduce the risk of cardiovascular disease in diabetic patients by improving diabetic dyslipidemia with the use of combination therapy failed, supporting the need to identify novel ways to treat diabetic dyslipidemia and to simultaneously target all major components of the metabolic syndrome. The mission of my laboratory is to investigate the molecular mechanisms causing gender and sex specific differences in diabetic dyslipidemia. The laboratory uses a wide range of techniques spanning biophysical chemistry, molecular biology, protein biochemistry, cell biology and animal physiology to understand the role of lipoproteins in cellular metabolism and the immune system response.
Sex specific differences in splenic immune response to western diet feeding
Chronic inflammation is a major feature of metabolic diseases in both, men and women. It is also acknowledged that sex differences are evident in the immune response to antigen regardless of origin. However, it is currently unknown how sex differences affect the immune response in metabolic diseases such as diet-induced obesity (DIO) and diabetes.
The spleen is the major organ for B-cell maturation and differentiation in men and mice. Here, the B-cell response upon sterile inflammation and against antigen is initiated. Splenocytes from obese mice, for instance, secrete cytokines geared towards a pro-inflammatory profile while their lean counterparts generate an anti-inflammatory cytokine profile. In addition, B-cells from obese animals exacerbate chronic inflammation by promoting pro-inflammatory T-cell populations in the periphery.
Our project aims to determine whether western diet feeding affects the splenic response in male and female mice differentially. Our preliminary data show that DIO female C57BL/6J mice have greater spleen:body mass ratios compared to cohorts of DIO male C57BL/6J mice. Phenotypical analysis of splenocytes isolated from male and female mice identified an activated B-cell subset being greatly enlarged in the DIO male cohort, but virtually absent in the female counterparts. In addition, array analysis of blood identified a number of differently expressed inflammatory markers between the cohorts.
To address our scientific aim the PhD student will perform immunohistochemistry and immunofluorescence on sections of spleens isolated from male and female mice fed western diet for up to 6 months. He/she will also apply state of the art flow cytometry analysis on splenocytes from these cohorts. To investigate underlying mechanisms of B-cell subset activation the PhD student will perform ex vivo B-cell and T-cell activation assays. In parallel he/she will detect and monitor DIO-specific cellular immunity by Enzyme Linked Immuno Spot Assay, a sensitive and accurate detection method for the visualisation of rare antigen-specific T or B cells within the immune cell populations of the spleens.