The goal of this research is to develop a new flow cytometry-based test for the clinical measurement of proangiogenic T cells. Such an assay does not exist today. Proangiogenic T cells, including angiogenic T cell (Tang) and Th17 subsets, participate in reparative mechanisms in the vasculature, in oncogenic angiogenesis and in other processes central to the overall health of the vascular system. The T cell test could be deployed as a stand-alone diagnostic tool but will ultimately provide the final core module of the Cytometric Vascular Health Profile (CytoVasHP), a cell-based blood test for the assessment of vascular health. The cardiovascular community has realized that patients who present with similar risk of cardiovascular disease often end up developing (or not) a range of pathologies with different morbidity, mortality and responses to therapy. To determine the most effective care for individual patients and to identify those most likely to benefit from specific interventios for prevention or treatment, there is an urgent need for new methods and tools that can account for individual patient differences and provide a comprehensive measurement of vascular health status. The addition of this new assay to the CytoVasHP will substantially increase the information potential of the profile. Millions of people worldwide could benefit from the development of the CytoVasHP. Cardiovascular disease (CVD) prevalence in the USA is 37% among adults and is projected to increase by 10% over the next 20 years. CVD risk factors such as obesity, hypertension and diabetes have a high prevalence worldwide, exacerbated by aging populations in the developed world and by changing diets and cultural habits in the developing countries. CytoVasHP is a multicomponent clinical assay that will integrate a number of cellular biomarkers of genetic and environmental risk factors (including vascular microparticles (MPs) and endothelial progenitor cells (EPCs)) with a unique and powerful pattern-discerning computational method. Measurement of proangiogenic Tang and Th17 will be a core component of the comprehensive measure of vascular health offered by CytoVasHP. The test will use flow cytometry and biocomputation to yield the CytoVasHP, which could be deployed in the drug development environment to inform pharmaceutical companies of potential vascular benefits or toxicities of new candidate therapeutics. Ultimately, the CytoVasHP will be ordered in the clinic for asymptomatic individuals being considered for cardiovascular preventive treatment, for assessing therapeutic effectiveness in patients being treated with cardiovascular drugs, or to assess cardiovascular toxicities as a side effect of other therapies. This project will develop a single tube flow cytometric panel to quantify proangiogenic T cells, Tang and Th17, composed of CD3, CD4, CD31, KDR, Il23R, CD 161, and CD184 (CXCR4) measurements. Laboratory protocols for sample preparation and data acquisition will be combined with the refinement and adaptation of a high dimensional computational approach for clinical interpretive analysis.
This proposal will provide a new way to manage healthcare for people with, or at risk of, certain heart and blood vessel diseases (such as atherosclerosis). Presently, healthcare for these people relies on the development of symptoms, by which time options are limited. The product that will be developed here will help to evaluate risk before symptoms develop, guide treatment decisions, and assess response to treatment.