Nanoscale particles in serum play critical roles in biological processes, including intercellular signaling, immune response, and the pathophysiology of important diseases such as cancer. One such disease is Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)-a clinical entity that is observed in a majority of the ~20 million Americans with CKD. CKD-MBD promotes vascular calcification that leads to progressive cardiovascular dysfunction, and significantly contributes to the exceedingly high rate of cardiovascular morbidity/mortality observed in this population. In CKD-MBD, the formation of soluble nanoscale calciprotein particles (CPPs) in serum mitigates the toxicity of hyperphosphatemia by sequestering calcium phosphate crystals and preventing their precipitation in the vasculature. Exciting recent discoveries have shown that CPP concentrations increase with CKD progression, and are not routinely observed in patients with normal kidney function. CPPs may thus represent a novel biomarker for identifying patients at high risk for progressive vascular calcification prior to the onset of irreversible mineralization f the vasculature. However, characterization of CPPs to date has been hindered by an inability to efficiently measure these nanoparticles in clinical samples. Spectradyne has developed a powerful platform instrument, the nCS1, which accurately measures the size and concentration of polydisperse nanoparticles in complex matrices such as serum. The technology is ideally suited to characterize biological particles as indicators of health and disease. Spectradyne proposes to collaborate with researchers at the University of Kansas Medical Center (KUMC) to build a version of this instrument for quantification of CPPs in serum. Together the combined team will investigate the potential of using the size distribution of particles in serum samples to predict the risk for vascular calcification in mice and humans, with the long-term goal of improving diagnosis and prevention of this condition. To accomplish these goals, two specific aims will be met.
In Aim 1, the instrument will be configured for measurements of serum nanoparticles: Sample preparation, the instrument itself, the analysis cartridge, and the data analysis software will all be optimized for measuring nanoparticles in serum. Cartridge production will also be increased for the study.
Aim 2 will evaluate the ability of the reconfigure instrument to measure CPPs in sera from humans and mice at high risk for vascular calcification. To achieve this we will: A) Quantify serum CPP concentrations and associated vascular calcification in two murine models; and B) Compare serum CPP levels in CKD patients and healthy controls, and associate with traditional mineral metabolism markers. Completion of this work will yield a user-friendly bench top instrument capable of rapid, high-resolution particl analysis in serum samples. Moreover, the utility of the instrument for the quantification of serum CPPs will be evaluated, and the role of this novel biomarker in the pathophysiology of vascular calcification determined.
Nanoscale particles in serum play a significant role in a broad set of biological processes that contribute to the development of important human diseases. Patients with decreased kidney function exhibit a disproportionate burden of calcium-phosphate buildup in their arteries (vascular calcification), which ultimately results in these patients suffering from a much higher rate of heart failure and death when compared to the general population. Recent evidence suggests that patients with decreased kidney function exhibit elevated blood levels of microscopic calcium-phosphate crystals called calciproteins that may promote vascular calcification formation. This project will further develop a revolutionary instrument for detecting calciproteins and other nanoparticles directly in blood, and thoroughly evaluate the utility of these particles as a diagnostic tool to promote the earlier diagnosis and improved treatment of vascular calcification in patients with kidney disease.
