The composition of the blood proteome provides indications of normal health and the presence of disease.
Over 90% of non-albumin proteins in the blood of mammals are N-glycoproteins bearing N-glycan structures
produced in the Golgi apparatus prior to nascent glycoprotein secretion. We have previously discovered an
intrinsic mechanism controlling the half-lives and thereby abundance and function of circulating blood
glycoproteins. This mechanism is linked to the progressive glycosidic remodeling of nascent blood
glycoproteins by circulating exo-glycosidases thereby resulting in the exposure of cryptic endocytic lectin
receptor ligands. Endocytic lectin receptors are highly conserved among mammals and are expressed on the
surface of various vascular and organ cell types where they recognize and bind their ligands from among
circulating blood components and glycoproteins. We have found that this intrinsic mechanism of blood
glycoprotein remodeling and clearance by lectin receptors is targeted by pathogens and the resulting changes
in blood glycoprotein abundance are linked to disease onset. Lectin receptor ligands include glycosidic
linkages of galactose, N-acetylglucosamine, fucose, or mannose; however, glycoproteins bearing physiological
lectin receptor ligands remain mostly unknown and thus the functions of lectin receptors are also mysterious.
This laboratory has developed an approach to identify physiological blood glycoprotein ligands of individual
lectin receptors by chromatography and mass spectrometry protocols. A subset of mammalian lectin receptors
bind to glycosidic linkages bearing exposed mannose, herein termed mannosylated blood glycoproteins. This
laboratory discovered in past related studies that the accumulation of mannosylated glycoproteins due to
defects in N-glycan synthesis causes chronic inflammation, autoimmunity, and degenerative disease. Normally
however, the recognition and clearance of mannosylated blood glycoproteins involves the expression and
function of mannose binding lectins including Mrc1. This proposal addresses the hypothesis that Mrc1 controls
the levels of mannosylated blood glycoproteins in normal physiology and protects against the onset of disease.
Our supporting data demonstrate that Mrc1 has a blood ligand repertoire including key regulators of the
vasculature. Absence of Mrc1 results in the accumulation of mannosylated Renin and Angiotensin Converting
Enzyme with elevated blood pressure. In addition, accumulating mannosylated Myeloperoxidase in the blood is
associated with vascular inflammation, blood-brain barrier breakdown, tissue damage, and autism-like
features. The roles of Mrc1 ligands will be addressed with inhibitors. In the blood of humans, we have further
discovered a link between individuals with low levels of mannosidase activity and high levels of mannosylated
blood proteins. This proposal in summary will investigate how the accumulation of mannosylated blood
glycoprotein ligands in Mrc1 deficiency cause disease and establish whether humans bearing high levels of
mannosylated blood glycoproteins similarly contain elevated markers of inflammation and vascular defects.