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Development of a Novel Technology for Preparative Fractionation and Characterization of Lipoprotein Particles

脂蛋白颗粒制备分级分离和表征新技术的开发

基本信息

批准号：
10708003
负责人：
Angela M Zivkovic
金额：
$ 30.36万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-25 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708003
关键词：
Activities of Daily Living Acute Disease Address Affinity Age Antioxidants Apolipoprotein A-I Apolipoproteins Behavior Binding Biological Biology Biomedical Research Cardiovascular Diseases Characteristics Chemicals Cholesterol Esters Chronic Chronic Disease Clinical Communities Complement Complex Coupled Data Development Diagnostic Diameter Disease Ethnic Origin Excision Exclusion Exposure to Fractionation Glucose Health Heterogeneity High Density Lipoproteins High Pressure Liquid Chromatography In Vitro Individual Knowledge Lipids Lipoprotein (a)Lipoproteins Longevity Mass Spectrum Analysis Measurement Measures Mediator Metabolic Clearance Rate Methods Mission Modification Molecular Molecular Sieve Chromatography Names National Institute of General Medical Sciences Nature Nerve Degeneration Nuclear Magnetic Resonance Optics Oxidants Particle Size Performance Physiological Plasma Polysaccharides Protein Analysis Proteins Publishing Refractive Indices Research Research Personnel Sampling Sepsis Series Signal Transduction Structure System Technology Therapeutic Transmission Electron Microscopy Validation Woman acute infection blood-brain barrier crossing detector experimental study gel electrophoresis glycation glycosylation immunoregulation improved innovation instrument instrumentation light scattering men mortality new technology oxidation particle receptor reconstitution theories therapeutically effective

项目摘要

Project Summary High-density lipoproteins (HDL) are the single strongest predictors of longevity and protect against a wide array of diseases, from chronic conditions like cardiovascular disease and neurodegeneration, to acute infection and sepsis mortality, and everything in between. If we can get HDL right, we can live long, healthy lives. Yet despite over 50 years of research, HDL have remained an enigma and therapeutic approaches for improving HDL function have proven elusive. HDL are highly heterogeneous and difficult to isolate and characterize because of their colloidal, multi-molecular nature yet very small size (< 20 nm in diameter). A critical barrier to progress is the lack of technologies to simultaneously quantify the size and number of HDL particles, and isolate them such that they remain intact and amenable for a variety of both compositional and functional analyses. The objectives of this project are to gain new technological knowledge on the application of our instrument using size exclusion chromatography coupled with multiple inline static and dynamic optical detectors, and to measure the quantitative advantages of this technology over state-of-the-art approaches for the isolation and physicochemical characterization of HDL particles. In particular, this project will solve the critical problem of quantifying the number of particles using a non-destructive approach that simultaneously measures and fractionates the particles by size, making it possible to evaluate the function and composition of different size-based HDL subclasses on a per particle basis. Currently, researchers are limited by the simple problem of not having a good denominator: the only option is to express the amount of an important constituent or functional capacity in the HDL we have measured based on a rough substitute for “concentration” (e.g. total protein in the isolated fraction). Therefore, if there is more of a certain protein (or higher functional capacity) in sample A vs. B, there is no way to distinguish whether that is simply because sample A has more particles in it or whether there are more molecules of that protein (or higher functional capacity) per particle. Different sizes of HDL carry different absolute and relative amounts of individual proteins, lipids, and other components, from as few as 2 molecules of the main apolipoprotein, apolipoprotein A-I, and 12 molecules of cholesteryl ester in the smallest HDL, to as many as 4-6 molecules of apolipoprotein A-I and hundreds of molecules of cholesteryl ester, with similar variability in the concentrations of other critical components that confer dozens of functions, from antioxidant, to immunomodulatory, to anti-proteolytic to name a few. And because particle size determines binding affinity to receptors, clearance rates, and likely even whether HDL can cross the blood-brain-barrier, knowing the number of particles of different sizes, and also the per particle composition of the cargo they carry is critical to the development of sensitive, actionable diagnostics, and targeted, effective therapeutics. Thus, the technology developed in this project will profoundly enable the biomedical research community to answer critical questions about HDL functional biology across a broad array of clinical and therapeutic applications.

项目总结