Boston University Medical Campus
Medicine

In general, the Molecular Genetics Unit’s research interests focus on determining the role apolipoproteins and lipoproteins play in relation to atherosclerosis and Alzheimer’s disease. The Unit is under the direction of Vassilis Zannis, Ph.D., Professor of Biochemistry. Investigations in his laboratory are focused on apolipoprotein gene regulation in vivo using antisense and transgenic methodologies, as well as adenovirus-mediated gene transfer. The project focuses on 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.

In addition, the elucidation of the structure-function relationship of human apoA-I and apoE and their relevance to cardiovascular disease and Alzheimer’s disease, respectively, are under investigation using in vitro mutagenesis, transgenic, and gene transfer methodologies. Pertinent questions are the role of apoA-I in the biogenesis and the functions of HDL, the role of apoE in cholesterol and triglyceride homeostasis in the circulation, the role of apoE in lipid homeostasis in the brain, and the pathogenesis of Alzheimer’s disease.

Individual junior faculty members on Dr. Zannis’ team are targeting various investigations. Horng-Yuan Kan, Ph.D., Research Assistant Professor of Medicine, is researching the analysis of the in vivo functions of apoA-I using adenovirus-mediated gene transfer and the transcriptional regulation of the ABCA1 transporter.

Eleni Zanni, Ph.D., Research Assistant Professor of Medicine, is working on the effect of diet and lipid-lowering drugs on the expression of genes that affect HDL biogenesis and HDL functions in a transgenic mouse model. Irina Gorshkova, Ph.D., Instructor of Medicine, is centering her research on the physicochemical analysis of the structure and stability of mutants of apoA-I and apoE. Using adenovirus-mediated gene transfer, Kyriakos Kypreos, Ph.D., Instructor, is working on the analysis of ApoE function in cholesterol and triglyceride homeostasis in the circulation.

During the past year, the major research findings from Dr. Zannis’ laboratory include the development of transgenic mouse models that clarify how apoA-I is regulated by hormone nuclear receptors. This work has uncovered signaling mechanisms that regulate the apoA-I and apoCIII gene. These transgenic mice will be used to selectively switch on apoA-I and apoCIII, as well as to increase HDL levels and improve HDL functions in an in vivo setting. In addition, the laboratory has found – using adenovirus-mediated gene transfer – that truncated apoE forms correct high levels of cholesterol without causing high triglyceride levels in mice. These truncated apoE forms may find therapeutic applications in the correction of genetic removal disorders. The laboratory has also generated transgenic mice that express apoE in the brain. These mice will be used to assess the effect of apoE in the pathogenesis of Alzheimer’s disease.

The laboratory, in collaboration with Monty Krieger, Ph.D., of the Department of Biology at the Massachusetts Institute of Technology, has established investigations focused on the functional interactions of lipid-bound apoA1 with the HDL receptor (SR-B1). This study has already established functional interactions of lipid-free apoA1 with the ABCA1 transporter and has shown that mutations in apoA1, which inhibit functional interactions, inhibit the biogenesis of HDL in vivo.

Research in the laboratory of Nelson Ruiz-Opazo, Ph.D., Professor of Medicine, is generally focused on the molecular genetic analysis of hypertension and novel receptors relevant to hypertension. Ongoing investigations include the identification of hypertension susceptibility genes in animal models of this disease, currently focusing on the Dahl S/Dahl R hypertensive rat model and in humans. This research has led to the identification of susceptibility genes for hypertension target organ-complications like hypertensive renal disease and cardiac hypertrophy. In addition, both in vitro and in vivo functional analysis of novel AngII, AVP, and ET-1 receptors, including the AngII/AVP dual receptor and the ET-1/AngII dual receptor, have been initiated. Dr. Ruiz-Opazo has begun studies on the determinants of learning and memory in the Dahl S/Dahl R rat model.

Victoria Herrera, M.D., Associate Professor of Medicine, is also working in the area of the molecular genetics of hypertension and cardiovascular disease. Current investigations are focused on the exacerbation of atherosclerosis by hypertension. In particular, Dr. Herrera is dissecting the pathways involved in vulnerable plaque development and destabilization through an integrated approach using histopathology, transcriptomics, proteomics, in vivo pathway testing. In addition, she is involved in the identification of genetic modifiers of hyperlipidemia relevant to gender and genetic background differences through total genome search for putative quantitative trait loci in F2 intercross hybrids and transcription profiling, and the identification of the pathways of salt sensitivity through differential transcription profiling of strategic inbred transgenic rats. The studies’ long-term goal is focused on the development of understanding, at the molecular level, the underlying differential susceptibility to coronary lesion development through gene expression profiling.