Research Interests

Nobuyo Maeda

My first project concerns the molecular pathology of atherogenesis. To better understand the involvement of lipoproteins in atherogenesis, I have been generating mice carrying mutations in the genes involved in lipid metabolism using homologous recombination in embryonic stem cells. Mice genetically altered develop spontaneous atherosclerosis. Influence of other genetic and dietary factors on progression of atherosclerotic lesions is being studied. 

My second project is aimed at a better understanding of how variations of genes are generated, particularly in multi-gene families. I am using the haptoglobin gene family as a model in which to study how a multi-gene family arises, how its members diverge in their structure, how some members evolve to have different functions, and how some lose their function and become pseudogenes.  

Oliver Smithies

Work in my laboratory over the past 10 years has focused on developing animal models of human genetic diseases. Homologous recombination (gene targeting) is used to alter a chosen gene in a pre-planned manner in mouse embryonic stem cells (ES cells) while they are in tissue culture. The genetically altered ES cells are then injected into normal mouse blastocysts which are introduced into pseudo-pregnant mice to complete their development. Chimeric mice are born which transmit the altered gene to their offspring. By the use of this procedure, they have made mouse models of cystic fibrosis (one of the most frequent single gene defects in Caucasians) and of Éø-thalassemia and É¿-thalassemia (among the most frequent world-wide single gene defects).

More recently we have been working towards understanding the genetics of essential hypertension - a complex disease with strong multigenetic and environmental components. Currently we have shown that genetic changes which affect the level of expression of the genes coding for angiotensinogen (AGT), or for renin, or the type 1a receptor for angiotensin II (Atr1a), or the endothelial form of nitric oxide synthase (eNOS), or the atrial natriuretic factor (ANF) or two of its receptors (NPRA and NPRC) affect blood pressures in the mouse. Surprisingly, comparable changes in the gene coding for the angiotensin converting enzyme (ACE) do not alter blood pressures. By the use of computer simulations, we have been able to uncover the theoretical basis for this unexpected result. These several findings are of considerable help in understanding how genetic factors influence blood pressure in humans. The mouse system is particularly valuable because the effects of combinations of genetic changes can be studied, and because environmental influences (such as salt intake) can be varied in a controlled fashion. Our most recent work is using these animal models to understand the genetic basis for differences in the risk of kidney damage in diabetic individuals.

Michael Altenburg

Apolipoprotein e is an important protein in lipid metabolism. It is a ligand for the low density lipoprotein receptor.  There are three main isoforms of apolipoprotein e designated E2, E3 and E4. We have replaced the the endogenous mouse apoe gene with each of the human alleles. I am studying the effects of these alleles on lipid meatbolism and atherosclerosis in mice.

Yau-Sheng Tsai

My research is aimed to understand why the gene defect in peroxisome proliferator-activated receptor-gamma (PPAR-gamma), factor to regulate glucose and lipid homeostasis, can cause different metabolic syndromes and cardiovascular abnormalities, such as atherosclerosis, diabetes mellitus, obesity, and hypertension.

Leighton James

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