Rotation Projects- Dr. Kaori Yamada

Rotation Projects

Research Interests Regulation of the cell function via trafficking of signaling molecules

The important question in my research is how cellular function is dynamically regulated by local activation of cell signaling. To induce the signaling locally, the signaling molecules need to be accumulated at the particular area of the cells. The accumulation of the molecules is mediated by the intracellular trafficking by the molecular motors; kinesins, dyneins, and myosins. Among them, we are particularly interested in the kinesin family protein, KIF13B, as it transports essential signaling molecules, such as VEGFR2.

Trafficking of VEGFR2 by KIF13B is critical for angiogenesis, forming the new blood vessels from pre-existing vessels. Angiogenesis is a hallmark of cancer and blinding eye diseases such as wet age-related macular degeneration (wet AMD) and diabetic retinopathy. Pathogenic angiogenesis is induced by an excess amount of vascular endothelial growth factor (VEGF) in the diseased tissue. To respond to VEGF, VEGFR2 needs to be exposed at the cell surface of endothelial cells. We found that a kinesin motor KIF13B mediates the trafficking of VEGFR2 to the cell surface. Based on the finding, we developed a small peptide inhibitor disrupting the interaction between VEGFR2 and KIF13B, thus inhibiting VEGFR2 trafficking. This peptide inhibitor successfully inhibited pathological angiogenesis in wet AMD and cancer. VEGF also induces vascular leakage, which causes inflammation in wet AMD and diabetic retinopathy, and metastasis in cancer. Our projects focus on understanding the role of intracellular trafficking in cell function.

One of our projects focuses on the role of VEGFR2 trafficking in dynamic cell sprouting in angiogenesis. Using live-cell imaging of VEGFR2 in sprouting angiogenesis, we will tackle the exciting questions; how the trafficking is regulated, how the direction of the trafficking is decided, and what happens if the trafficking is activated or blocked. Another project focuses on the role of VEGFR2 trafficking in vascular leakage during transmigration of metastatic cancer cells. Using in vitro transmigration models, we will investigate the mechanism of regulating vascular leakage and develop a strategy to prevent cancer metastasis. Moreover, using the mouse models of endothelial-specific KIF13B knockout and the aforementioned pharmacological inhibitor in disease models, such as cancer models, wet AMD models, and diabetic retinopathy models, we will address the role of the trafficking in progression of diseases, and whether we can develop the strategy to regulate the trafficking to inhibit pathological angiogenesis in these diseases.

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