Major Current Research Interests:
1. Transcriptional regulation of the human apolipoprotein genes in vivo using transgenic mouse models and recombinant viral-mediated gene transfer.
2. Structure and functions of the human apolipoproteins: roles of apoE and apoA-I in cholesterol and triglyceride homeostasis and of apoE in Alzheimer’s disease.
3. Effect of genetic and environmental factors on apolipoproteins and their effects on the pathogenesis of atherosclerosis.
A. Description and Scope of the Research Projects
Lipoproteins are macromolecular complexes of lipids and apolipoproteins, which are involved in cholesterol transport and cholesterol homeostasis. During the past 15 years, our laboratory has cloned most of the apolipoprotein cDNAs and/or genes and has described genetic variations in apolipoproteins that are associated with human diseases. We have also identified the regulatory elements which are involved in the regulation of transcription of the apoA-I, apoA-II, apoA-IV, apoB, apoCII and apoCIII genes and several factors bound to them, and have assessed their importance for hepatic and intestinal transcription.
Currently, we have two major research objectives:
1. Mechanisms of transcriptional regulation of the apolipoprotein genes in vivo and in vitro. This includes
a) elucidation of the role of hormone nuclear receptors and factors bound to the apoCIII enhancer on the transcriptional regulation of the apoA-I, apoCIII, and apoA-IV gene cluster;
b) elucidation of the importance of the hormone nuclear receptors and apoCIII enhancer for apolipoprotein gene regulation in vivo using in vivo footprinting, antisense methodologies, and transgenic mice. The combined in vitro and in vivo approaches may provide new insights on the mechanisms responsible for apolipoprotein gene regulation that may affect the plasma apolipoprotein and lipoprotein levels.
2. Elucidation of the structure-function relationship of human apoA-I and apoE.
a) by in vitro mutagenesis of the corresponding genes and analysis of the properties of the protein products;
b) by using transgenic methodologies. ApoA-I is involved in the reverse transport of cholesterol and the activation of the enzyme LCAT. ApoE is responsible for the clearance of lipoprotein remnants and recently has been implicated in Alzheimer's disease. Pertinent questions are: domains of the two proteins involved in lipid and receptor binding, in activation of enzymes, as well as the role of apoE in the pathogenesis of Alzheimer's disease.
B. Potential Benefit to the Public
The discovery of changes (mutations) in proteins, which can cause high plasma cholesterol, permits early diagnosis of the carriers by new protein and DNA tests that are 100% accurate.
Some of the new genes that have been isolated may in the near or distant future be used for manufacturing proteins or protein derivatives that have beneficial pharmacological properties or in gene therapy.
Understanding how we can control the synthesis of certain proteins, for instance apoA-I and apoE, may lead to the development of new drugs for the prevention and/or treatment of cardiovascular disease.
Understanding how apoE functions may help in the development of new drugs for slowing down or the prevention of Alzheimer's disease.
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Last updated: July 9, 2002