Date: September 26, 2008

Time: Noon to 1:00

Title: "Neurotrophins-mediated Signaling Cascades in Neuronal Survival"

Speaker: Keqiang Ye, PhD
Associate Professor, Pathology and Laboratory Medicine
Emory University School of Medicine

About the Talk:
Neurotrophins, through Trk receptors, mediate neuronal survival, differentiation, synaptic plasticity and neurogenesis. Among numerous signaling cascades initiated by neurotrophins, PI 3-kinase/Akt is essential for neuronal survival. However, the biological functions of nuclear PI 3-kinase cascades remains incompletely understood. We show that PIKE, a nuclear GTPase that upregulates PI 3-kinase, plays an critical role in mediating this process.  Clinical studies demonstrate that NGF and BDNF are not pharmacokinetically optimal for use as a therapeutic agent. To mimic their functions pharmacologically, we developed a high-throughput screening assay to search for small molecular TrkA/TrkB agonists. One of the most potent compounds, strongly bound TrkB receptor and provoked its dimerization and autophosphorylation, leading to downstream signaling cascades activation. Administration of this compound into mice substantially inhibited kainic acid-induced neuronal cell death and decreased infarct volumes in the transient middle cerebral artery occlusion (MCAO) model of stroke. Further, this small molecule displayed evident anti-depressive activity. Thus, 7,8-dihydroxyflavone imitates BDNF and acts as a robust TrkB agonist, which might provide a powerful therapeutic tool for treatment of a variety of neurological diseases.

Where: John D. Wiley Conference Center
Room T216, Second Floor, North Tower

For Further Information: Contact Teresa Palumbo at 263-5837 or palumbo@waisman.wisc.edu

This Seminar Series is partially funded by the John D. Wiley Conference Center Fund, the Friends of the Waisman Center and NIH grant P30 HD003352.