Cardiovascular disease (CVD) is the number one killer in the United States. An unfavorable lipoprotein profile is the primary risk factor for atherosclerosis, the condition that underlies over 70% of CVD deaths. The vast majority of medical therapy (statins) is directed toward one molecular target (HMG-CoA reductase). The goal of these drugs is to improve the lipoprotein profile and consequently the cardiovascular risk of the patient. However, optimal cardiovascular risk reduction often requires combination therapy, and the choices for such combinations are limited. New drugs directed at novel targets are needed in the fight against CVD. Lipoprotein receptors (i.e. LDL-R, LRP, SR-BI) play a central role in the development of atherosclerosis, and drugs targeted against these receptors may be beneficial in cardiovascular risk reduction. However, these receptors are difficult to study in meaningful drug target assays. Integral Molecular has developed a technology, the lipoparticle, which enables membrane proteins to be purified away from the surface of a cell while maintaining their structural integrity. In this Phase I application, we propose to create lipoparticles containing the full-length low-density lipoprotein receptor (LDL-R). We will create, characterize and test LDL-R lipoproteins in two specific aims.
Specific Aim 1 : Construct and test lipoparticles containing LDL-R. In this aim, we will create LDL-R lipoparticles and compare them to alternative receptor reagents (receptor expressed in live cells, and soluble receptor fragments) using standard ELISA and radioligand techniques.
Specific Aim 2 : Create and validate biosensor-based analysis of LDL-R lipoparticles. In this aim, we will use LDL-R lipoparticles on the optical biosensor platform with the goal of measuring ligand-binding kinetics. ? ?
| Sachais, Bruce S; Rux, Ann H; Cines, Douglas B et al. (2012) Rational design and characterization of platelet factor 4 antagonists for the study of heparin-induced thrombocytopenia. Blood 119:5955-62 |
