Nathan O. Stitziel, M.D., Ph.D.
ABSTRACT:
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 interactions may reduce risk of these age-associated diseases and enhance longevity. Although the cellular receptor responsible for mediating the effect of SVEP1 was previously unknown, our studies in the first year of LLF funding have found a novel high affinity interaction between SVEP1 and the orphan receptor PEAR1 which is highly expressed by endothelial cells and vascular smooth muscle cells. SVEP1 binding to PEAR1 activates canonical PEAR1 signaling ultimately leading to activation of the PI3K/Akt/mTOR pathway. Given the role of mTOR signaling in cellular senescence and vascular aging, this novel receptor/ligand interaction may represent the mechanism to explain how SVEP1 levels influence its myriad diseases of vascular aging. In this proposal, we will characterize how SVEP1 interacts with PEAR1, thereby generating foundational preliminary data which will be used to pursue funding in addressing how SVEP1 might be targeted. In Aim 1, we will define which region(s) of SVEP1 interacts with PEAR1 to activate its canonical signaling pathways and will determine if inhibiting that interaction abrogates SVEP1’s effects on intracellular signaling. In Aim 2, we will develop a method to quantitatively measure levels of SVEP1 which will position us to measure protein levels in healthy and diseased tissues, thereby allowing us to further
characterize and refine the role of SVEP1 as a causal biomarker in diseases of aging. Our investigative team has developed preliminary data to support the proposed studies which are poised to reveal the mechanisms by which SVEP1 influences age-associated diseases with the potential to uncover novel therapeutic approaches.
LAY SUMMARY:
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. Although the cellular receptor and signaling pathway responsible for SVEP1’s role in the pathophysiology of these diseases was previously unclear, we recently identified a high affinity interaction between SVEP1 and a cell surface receptor named PEAR1. The action of SVEP1 binding to PEAR1 induces cellular signaling pathways associated with longevity and aging. In this proposal we will assess how SVEP1 interacts with this novel receptor and develop a method to measure levels of SVEP1. Through these studies we will expand our understanding of how this protein influences disease and the therapeutic potential of targeting SVEP1 as a treatment for many age-associated diseases.
