Nathan Stitziel, M.D. Ph.D.
Project Overview:
SVEP1 has emerged as a novel circulating biomarker of age and longevity in humans that is causally associated with risk of multiple age-associated chronic diseases. The mechanisms underlying the role of SVEP1 in the pathophysiology of these diseases, however, remain unknown. In this proposal we will assess how circulating SVEP1 influences the behavior and cellular signaling of endothelial cells, a key cell type involved in the SVEP1-associated diseases which is constantly exposed to circulating proteins. We will determine which of its protein interactions are required for its effects, thereby expanding our understanding of how this protein influences disease and the therapeutic potential of targeting SVEP1 as a treatment for these age-associated diseases.
Progress Report
A series of recent human genetic studies have found a causal link between the circulating levels of the protein SVEP1 with multiple age-associated chronic diseases including coronary artery disease, hypertension, diabetes, and dementia. Perhaps due to its underlying role in these age-associated diseases, the plasma levels of SVEP1 significantly increase with age in an accelerating fashion and increased levels of the protein are causally associated with decreased longevity. Thus, the available evidence suggests that decreasing levels of SVEP1 or inhibiting its function may reduce risk of these age-associated diseases and enhance longevity. However, how circulating SVEP1 influences disease is unknown.
Our preliminary results find that exogenous SVEP1 can induce cellular changes in human endothelial cells (ECs), including an increase in adhesion and proliferation along with an increase in integrin and Akt signaling. ECs play an important role in vascular disease and may represent the link to explain how plasma protein SVEP1 levels may influence disease. In the aims of this proposal, we will characterize how SVEP1 influences the cellular behavior of ECs, thereby generating foundational preliminary data which will be used to pursue funding in addressing how circulating plasma SVEP1 influences these age-associated diseases. In Aim 1, we will define which regions of SVEP1 mediate its influence on ECs and in Aim 2, we will determine which EC receptors mediate the influence of SVEP1 on the changes in cellular behaviors and intracellular signaling we have observed. Our investigative team has developed preliminary data to support all proposed studies which are poised to reveal the mechanisms by which SVEP1 influences age-associated diseases with the potential to uncover novel therapeutic approaches.
