PROJECT SUMMARY/ ABSTRACT. My research program focuses on understanding the cellular and
molecular mechanisms underlying the progression of tissue injury mediated by meprin metalloproteases.
Meprins comprise of two subunits, a and ß, which form two protein isoforms, meprin A (a-a or a-ß) and meprin
B (ß-ß) with distinct and overlapping substrates. Meprins are most abundantly expressed in the brush-border
membranes of proximal kidney tubules and small intestines. Meprins are also expressed in leukocytes
(monocytes and macrophages), podocytes, skin, endothelial cells, and cancer cells. Meprins have been
implicated in the pathophysiology of inflammatory- and fibrosis-associated diseases that include kidney
disease, inflammatory bowel disease, lung fibrosis, neurodegenerative disease (e.g. Alzheimer’s disease), and
cancer. Single nucleotide polymorphisms (SNPs) in the meprin ß gene were shown to associate with severity
of certain diseases such as diabetic kidney disease and cancer. My research group uses a combination of
molecular biology and proteomic approaches to identify meprin substrates and characterize the interactions
between meprin isoforms and their substrates. These are coupled with in vivo studies with meprin knockout
mouse models to determine how meprin activity impacts the progression of disease. Known meprin substrates
include extracellular matrix (ECM) proteins, modulators of inflammation (e.g. proinflammatory cytokines [IL-1ß,
IL-6, IL-18, MCP-1; and anti-inflammatory proteins Ac-SDKP), cell signaling proteins (e.g. protein kinase A and
protein kinase C), mediators of the hypoxia response (e.g. osteosarcoma-9), tight junction proteins (e.g.
claudin 5, occludin, E-cadherin, and Z0-1) cytoskeletal proteins (e.g. villin and actin) and proteins that
contribute to plaques in AD (e.g. amyloid precursor protein and triggering receptor expressed on myeloid cells
2). The diversity of meprins substrates suggests that complex mechanisms are involved under different
conditions and in different organs. It’s important to gain understanding of these mechanisms to facilitate
development of diagnostic and therapeutic tools. For the five year period of this proposal, we will conduct
studies in three areas; (i) to determine how SNPS in the meprin ß gene impact its interactions with substrates
and physiological sheddases, (ii) determine how meprin interactions with substrates modulate signaling
pathways and impact responses in hypoxia, inflammation, and ECM metabolism, and (iii) to evaluate the use of
meprin and meprin cleavage products as biomarkers for development of diagnostic tools for early detection of
disease. The proposed research will transcend basic (in vitro and in vivo) to gain insights on the basis for
genetic predispositions associated with meprins. Translational studies are also proposed to apply this
knowledge in development of diagnostic tools applicable to diabetic kidney injury and Alzheimer’s disease
(AD), an important step in advancing precision medicine. Furthermore, this award will facilitate mentoring of
trainees from underrepresented minority populations and thus promote diversity of the biomedical workforce.