2nd Annual HDL CHOLESTEROL - Metabolic Pathways and Drug Development

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Overview

During the 1st international conference, significant advances were presented towards the research and development of effective therapeutics for elevating the HDL Cholesterol level and lowering the risk of coronary heart disease. Once again, the 2001 conference showcases leading academic and industry researchers from around the world who will present the latest in exciting new discoveries to influence the HDL Cholesterol metabolic pathway, including such areas as:

Transfer proteins and receptors
* New CETP inhibitors
* Lipoprotein receptors as drug targets
Transcription Factors and Nuclear Receptors
* RXR as a possible drug discovery target
* The role of PPAR in cardiovascular diseases
Clinical and genetic studies
* HATS ¥ VA-HIT ¥ Genetic variations
ABC1 Transporter Protein
Expression and regulation of ABC1
* cellular trafficking of ABC1
Scavenger Receptor B Type 1
* Binding capacities, variants and regulation
* SRB1 and reverse cholesterol transport

Take advantage of this annual event designed specifically to give you the latest insight and in-depth information about the research in progress to develop novel therapeutic approaches for cardiovascular disease. Register early to reserve your place!

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Agenda

Monday, February 12, 2001

8:00 Registration, Poster/ Exhibit Set Up, Coffee & Danish

Clinical and Genetic Studies

8:55 Chairperson’s Opening Remarks
Jose M. Ordovas, Ph.D., Director Nutrition and Genomics Unit, Professor/Senior Scientist, JM-USDA-Human Nutrition Research Center on Aging at Tufts University

9:00 Candidate Genetic Variation Affecting Plasma HDL
Concentration
Robert Hegele M.D., Blackburn Scientist, Robarts Research Institute, Professor of Medicine and Biochemistry, University of Western Ontario, Ontario, Canada
An approach to identify a genetic determinant of a complex quantitative trait such as plasma HDL cholesterol is to study rare patients with an extreme monogenic phenotype, such as hypoalphalipoproteinemia. The causative gene in the monogenic form becomes a candidate determinant of the trait in the general population. Common single nucleotide polymorphisms within the candidate gene product can then be assessed for association with plasma HDL cholesterol concentration.

9:30 Niacin Plus Simvastatin Protect Against Atherosclerosis and Clinical Events in CAD Patients with Low HDL
Xue-Qiao Zhao, M.D., University of Washington
Do niacin plus simvastatin (NS(+)) benefits patients with CAD, average LDLc, high triglucerides, and HDLc<35mg/dl? The NIH-funded HDL Atherosclerosis Treatment Study (HATS), a double-blinded, placebo-controlled, 3-year angiographic trial, randomly assigned 160 such patients to NS(+) or placebos (NS(-)); the latter took 50 mg bid niacin to
blind for flushing. All patients received dietary and smoking counseling, and exercise training. The primary quantitative angiographic (QCA) endpoint was the group average change, per patient, in percent stenosis among the worst lesion found in each of 9 proximal coronary segments. The primary clinical endpoint (CE) was composite of coronary death, MI, stroke, or hospitalization ± revascularization for confirmed unstable ischemia. Conclusions: Niacin plus simvastatin have strikingly favorable effects in CAD patients with low HDL. Atherosclerosis progression is virtually halted
and clinical events are reduced by 70% with this regimen.

10:00 VA-HIT and the Benefit of Fibrates in Patients with Low HDL-C and the Metabolic Syndrome
Sander Robins, M.D., Professor of Medicine, Boston University School of Medicine
I will review the major findings of VA-HIT, a large, placebo-controlled, multicenter intervention trial with the fibrate, gemfibrozil, conducted in men with CHD and low HDL-C and prominent features of the metabolic syndrome. This trial demonstrated for the first time that CHD events could
be significantly reduced by drug therapy in patients with a low HDL-C and a low LDL-C by increasing HDL-C and without changing LDL-C

10:30 Refreshment Break and Poster/Exhibit Viewing

11:00 Class A amphipathic helical peptide analog protects mice from diet-induced atherosclerosis
G.M. Anantharamaiah, Ph.D., Professor of Medicine, Department of Medicine, UAB Medical Center*
Several synthetic peptide analogs have been shown to mimic many of the properties of human apo A-I in vitro. A new peptide (5F) with increasedamphipathicity, was given by intraperitoneal injection, 20ug/day, for 16 weeks to C57BL/6J mice fed an atherogenic diet. Mouse apo A-I (MO AI)(50ug/day) or phosphate buffer saline (PBS) injections were given to other mice as controls. Total plasma cholesterol profiles were not significantly different among three groups LDL from animals injected with 5F induced less chemotactic activity than LDL taken from controls in human artery wall cells. Compared to HDL from human apo A-I injected animals, HDL from MO AI injected animals was not effective in preventing LDL-induced chemotactic activity. Mice receiving peptide 5F had significantly less aortic atherosclerotic lesion area compared to mice receiving PBS or Mo AI We conclude that 5F may have potential in the prevention and treatment of atherosclerosis.*Other Collaborators: David W. Garber, G. Datta, M.
Navab and A.M. Fogelman

Transfer Proteins and Receptors

11:30 The Discovery of (Tertiaryamino)propanols as a New Simple Class of Potent Cholesteryl Ester Transfer Protein Inhibitors
James A. Sikorski, Ph.D., Science Fellow, Medicinal Chemistry, Pharmacia Discovery Research
Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that mediates the transfer of cholesteryl ester (CE) from HDL to VLDL with a balanced reciprocal exchange of triglycerides. CETP thus moves CE from HDL,
that is known to protect against coronary heart disease, into proatherogenic VLDL and LDL. (Tertiaryamino)propanols were recently discovered as a new simple class of potent and selective CETP inhibitors. High throughput screening identified an initial lead with modest micromolar activity. Further optimization produced low nanomolar inhibitors. The key structure activity relationships as well as in vitro and in vivo data for this new lead series will be presented.

12:00 Pharmacological profile of a Cholesteryl Ester Transfer Protein Inhibitor, JTT-705
Korekiyo Wakitani, Deputy General Manager, Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, JT Inc.
The role of cholesteryl ester transfer protein (CETP) in atherosclerosis remains unclear. We have developed a potent and specific CETP inhibitor, JTT-705, and investigated the effect of JTT-705 on atherosclerosis in cholesterol-fed rabbits. JTT-705 increased HDL-C, decreased non HDL-C and
inhibited the progression of atherosclerosis. Our findings indicate that CETP may be atherogenic in vivo and that JTT-705 may be a potential anti-atherogenic drug.

12:30 Lunch, sponsored by The Knowledge Foundation

Transfer Proteins and Receptors II

1:45 Cholesterol Absorption Inhibitors as Serum Cholesterol Lowering Agents
Yu-sheng Chao, Ph.D., Distinguished Senior Investigator, Department of Lipid Biochemistry, Merck Research Laboratories
Abstract unavailable at time of print

2:15 Endocytosis of HDL via the action of cubilin and megalin
W. Scott Argraves, Associate Professor, Department of Cell Biology, Medical University of South Carolina
Recent findings establish that megalin, a member of the low density lipoprotein receptor family, acts together with cubilin to mediate endocytosis of high density lipoproteins (HDL). In addition to summarizing these findings, new insights into the mechanism by which these receptors function in HDL uptake will be described. Other topics of discussion will include: a) the potential significance of megalin/cubilin-mediated uptake of HDL/lipid-poor apoA-I to processes such as plasma HDL homeostasis and embryonic development and 2) perspectives for the use of megalin and
cubilin as drug targets.

2:45 Refreshment Break and Poster/Exhibit Viewing

Transcription Factors and Nuclear Receptors

3:10 Chairperson’s Remarks
Jonathan D. Smith, Associate Professor, Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University

3:15 RXR:PPAR heterodimers as targets for drug development
Mark D. Leibowitz, Associate Director, Metabolic Disease Pharmacology, Ligand Pharmaceuticals, Inc.
The retinoid X receptor (RXR) is a ubiquitously expressed nuclear receptor that forms heterodimers with numerous other receptors such as the peroxisome proliferator-activated receptors (PPARs), thyroid hormone (TR), vitamin D (VDR), and retinoic acid (RARs). Many of these heterodimers play critical roles in metabolic regulation and therefore represent potential drug discovery targets.

3:45 PPAR Agonists as Therapeutic Agents in Disease
Dr. Kevin W. Buchan, Cardiovascular Systems, Glaxo Wellcome, Stevenage, Herts, UK
The discovery of potent, selective agonists for peroxisome
proliferator-activated receptors (PPARs) has resulted in a widespread interest in the therapeutic potential of these agents. The ability of PPAR agonists to impact upon cardiovascular pathophysiology through direct effects on the vessel wall, as well as through the modulation of risk
factors (such as dyslipidaemia and insulin resistance), will be discussed.

4:15 Refreshment Break and Poster/Exhibit Viewing

4:45 Transcription factors as regulators of HDL metabolism
Bart Staels, Professor of Pharmacy, U.325 INSERM,
Dept.de Atherosclerose, Institut Pasteur de Lille, and Faculte de Pharmacie, Universite de Lille
II, Lille, France
We have identified the nuclear receptors PPARa, RORa and Rev-erba as transcriptional regulators of HDL metabolism. These receptors act by influencing the transcription of genes determining HDL levels, such as apo A-I and apo A-II. In addition, absence of their expression profoundly perturbs HDL metabolism. Through genetic studies we have now identified a PPARa variant in humans, which may act as a dominant negative form. We speculate that individuals expressing high levels of this variant may be resistant to fibrates. Furthermore, we have determined the human PPARa
gene structure and identified several polymorphisms which are associated with altered serum lipid and apo A-I levels in type II diabetic patients. Altogether, these results identify nuclear receptors, such as PPARa, involved in the control of HDL metabolism. Further research will be aimed
at identifying pharmaceutical compounds which may prove of value in the treatment of hypoalphalipoproteinemia and other disorders of lipid and lipoprotein metabolism.

5:15 Downstream of the Nuclear Receptor: Utilizing Transcriptional Profiling for the Identification of Novel Genes and Pathways Involved in HDL Metabolism
Tom Logan, Ph.D., Scientist, Department of Cardiovascular Biology, Millennium Pharmaceuticals, Inc.
Abstract not available at time of print.

5:45 A Broad Role for the Zinc Finger Protein ZNF202 in Human Lipid Metabolism
Ben Bowen, Senior Fellow, Novartis Institute for Biomedical Research
The ZNF202 gene resides in a chromosomal region linked genetically to low HDL cholesterol in Utah families. The ZNF202 gene product is a transcriptional repressor that binds to elements found predominantly in genes that participate in lipid metabolism. Among its targets are
structural components of lipoprotein particle(apolipoproteins AIV, CIII, and E), enzymes involved in lipid processing and efflux (lipoprotein lipase, lecithin cholesteryl acyl transferase, and ABC1), and several
genes involved in processes related to energy metabolism and vascular disease. Based on the linkage and transcriptional effects of ZNF202, we propose
that ZNF202 is a candidate susceptibility-gene for human dyslipidemia.

6:15 End of Day One

Tuesday, February 13, 2001

8:30 Coffee and Danish

8:55 Chairperson’s Opening Remarks
Karen F. Kozarsky, Ph.D., Investigator, Cardiovascular
Pharmacology, SmithKline Beecham Pharmaceuticals

ABC1 Transporter Protein

9:00 ABC1 and Cholesterol Efflux, Lessons Learned from RAW264 Cells
Jonathan D. Smith, Ph.D., Associate Professor, Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University
cAMP treatment of the murine macrophage cell line RAW264 induces cholesterol efflux to apoAI and HDL. Taqman analysis of ABC1 mRNA revealed that cAMP induces ABC1 mRNA by >50 fold. We have made stably transfected
ABC1 antisense cell lines, and find that these decrease ABC1 mRNA and almost completely block the cAMP mediated induction of cholesterol efflux to ABC1 and HDL, proving that ABC1 mediates these cAMP effects on cholesterol efflux.

9:30 ABCA1-Mediated Secretion of Cellular Lipids
John F. Oram, Ph.D., Research Professor of Medicine, University of Washington
Lipid-poor HDL apolipoproteins remove cholesterol and phospholipids from cells by an active transport pathway controlled by an ATP-binding cassette transporter called ABCA1 (also ABC1). Studies of human disease and animal
models have shown that ABCA1 plays a critical role in transporting these lipids from tissues into the lipoprotein metabolic pathway. Thus, ABCA1 has become an important therapeutic target for mobilizing cholesterol from macrophages and preventing atherosclerosis.

10:00 Refreshment Break

10:30 ABC1: Expression and Regulation
Omar L. Francone, Ph.D., Senior Research Investigator, Pfizer Central Research
Recently, the human ATP-binding cassette transporter-1 (ABC1) gene has been demonstrated to be mutated in patients with Tangier Disease. Gaining insight into the role of ABC1 in vivo represents a fundamental step in understanding HDL metabolism, cholesterol trafficking, and disease. To address these questions, we used gene targeting in embryonic stem cells to create mice that lack ABC1.

11:00 Cellular Localization and Trafficking of Human ABCA1
Edward B. Neufeld, Ph.D., Research Fellow, National Heart, Lung and Blood Institute, Molecular Disease Branch
ABCA1 plays a critical role in apoA-I mediated efflux of cellular sterol and phospholipids, and when defective, causes Tangier disease. A functional ABCA1-GFP transporter was found to traffic between the plasma membrane and
endocytic vesicles. These results suggest that ABCA1-mediated lipid efflux may involve cycling of ABCA1 to the cell membrane through specific endocytic vesicles.

11:30 Lunch on your own

Scavenger Receptor B Type I

12:55 Chairperson’s Remarks
John F. Oram, Ph.D., Research Professor of Medicine, University of Washington

1:00 SR-BI - a Receptor for HDL and LDL
Karen F. Kozarsky, Ph.D., Investigator, Cardiovascular
Pharmacology, SmithKline Beecham Pharmaceuticals
The scavenger receptor, class B, type I (SR-BI) is capable of binding multiple lipoproteins. The HDL and LDL binding capacities of SR-BI will be considered in in relation to cholesterol efflux and influx, and how these properties may relate to the atheroprotective effect of SR-BI expression.

1:30 SR-BI: A Multilipoprotein Receptor with Multiple Phenotypes
Jose M. Ordovas, Ph.D., Director Nutrition and Genomics Unit, Professor/Senior Scientist, JM-USDA-Human Nutrition Research Center on Aging at Tufts University
The SR-BI is a multilipoprotein receptor shown to be important in HDL metabolism in rodents. We have found several SR-BI variants and investigated their association with lipids and other cardiovascular risk factors. Our results are consistent with the notion that variability at
this locus has significant effects over several lipid phenotypes. Moreover, we found associations with several anthropometric variables. Our data suggest that in humans the SR-BI could play also a role in energy balance.

2:00 Refreshment Break and Poster/Exhibit Viewing

2:30 Role of the HDL Receptor SR-BI in Hepatic Cholesterol and Bile Acid Metabolism
Attilio Rigotti, Assistant Professor, Gastroenterology Department, Catholic University School of Medicine, Santiago, Chile
SR-BI mediates selective HDL cholesterol uptake to the liver. Further studies of the role of SR-BI in cholesterol and bile acid metabolism in mice show that hepatic total and unesterified cholesterol contents were slightly increased in SR-BI-deficient mice, while sterol synthesis and LDL receptor expression were not significantly changed. SR-BI deficiency selectively impaired biliary cholesterol secretion, without concomitant changes in either bile acid pool size and composition or bile acid excretion. Thus, SR-BI plays a critical role in the last step of reverse
cholesterol transport which may explain its anti-atherogenic activity invivo.

3:00 Regulation and Role of CD36 in Atherosclerosis
Andrew C. Nicholson, Associate Professor of Pathology, Department of Pathology and Center of Vascular Biology, Cornell University Medical College
CD36 is a macrophage scavenger receptor that binds oxidized LDL (OxLDL),TSP, and apoptotic cells. OxLDL, M-CSF and IL-4 up-regulate expression of CD36, due, in part, to their ability to activate the transcription factor, PPAR-g. We investigated the effect of transforming growth factor-b (TGF-b)on expression of macrophage CD36. We demonstrated that TGF-b decreases CD36 expression by phosphorylation of MAPK, subsequent MAPK phosphorylation of PPAR-g, and decreased CD36 transcription by phosphorylated PPAR-g.

3:30 End of Conference

Call for Posters

Selected Oral Presentations and Call for Posters
Industry, government and academic researchers are encouraged to submit poster as soon as possible. One-page abstracts (8 1/2” x 11” with 1-inch margins) including title and authors must be submitted no later than January 6, 2001 for inclusion in the program course book. Additional poster submissions will be accepted until January 21, 2000 but may not be included in the course book. Note: The poster board reservation fee is $45. If you are submitting a poster, you MUST be registered and paid in advance to ensure that a poster board is reserved for you.

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