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Xiaojia (Sasha) Guo, PhD

Associate Research Scholar in Medicine (Nephrology)

Contact Information

Xiaojia (Sasha) Guo, PhD

Office Location

Mailing Address

  • Nephrology

    PO Box 208056, 333 Cedar Street

    New Haven, CT, 06520-8056

    United States

Research Summary

We are interested in the control of vascular remodeling. Endothelial and smooth muscle cell-derived neuropilin-like protein (ESDN) is up-regulated in the neointima of remodeling arteries and modulates vascular smooth muscle cell (VSMC) growth. Receptor tyrosine kinases (RTKs) constitute a family of cell-surface receptors, including PDGFR, EGFR, VEGFR, and FGFR, controlling a variety of cellular processes, such as proliferation, differentiation, migration, and survival. RTKs are activated by binding of extracellular ligands, resulting in increased tyrosine kinase activity and phosphorylation of target proteins. Once activated, RTKs are ubiquitinated, internalized and targeted for degradation to the lysosomal compartment or locally destroyed in proteasomes. Many of these processes are regulated by ubiquitination, a post-traslational modifi cation where the small protein ubiquitin is covalently attached to a target protein by ubiquitin ligases such as c-Cbl. While polyubiquitination marks proteins for proteasomal degradation, mono- or multi-ubiquitination is sufficient to direct endocytosis and lysosomal degradation of membrane receptors.

Specialized Terms: vascular remodeling, receptor tyrosine kinases (RTKs)

Extensive Research Description

We have shown that ESDN down-regulation by RNA interference significantly enhanced PDGF-induced VSMC DNA synthesis and migration. This was associated with increased ERK1/2, Src, and PDGF receptor (PDGFR) phosphorylation, without altering total PDGFR expression levels. In binding assays, ESDN down-regulation significantly increased 125I-PDGF maximum binding (Bmax) to PDGF receptors on VSMCs without altering the binding constant (Kd), raising the possibility that ESDN regulates PDGFR processing. ESDN down-regulation significantly reduced ligand-induced PDGFR ubiquitination. This was associated with a significant reduction in the expression level of c-Cbl, an E3 ubiquitin ligase that ubiquitinylates PDGFR. Thus, ESDN modulates PDGF signaling in VSMCs via regulation ofPDGFRsurface levels. The ESDN effect is mediated, at least in part, through effects on PDGFR ubiquitination.

Continued detailed analyses of the involvement of ESDN in the regulation of RTK-driven pathologies is thus predicted to pave the way for therapeutic strategy for vascular diseases and other diseases involving RTK-driven tissue remodeling.

Coauthors

Research Interests

Nephrology; Vascular Remodeling

Selected Publications