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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