Dr. Park’s study is focused on two proteins – Crk and CrkL – that are reported to be elevated in several types of human cancer, including glioblastoma, and correlated with poor prognosis. Tumor cell migration and invasion contribute to the spread of glioblastoma to healthy brain tissues, leading to high recurrence rates.

Dr. Park has established the real-time quantitative measurement of glioma cell migration upon gene knockdown or overexpression and demonstrated that Crk and CrkL play important roles in glioblastoma cell migration and invasion. Dr. Park is also working on the potential role of Crk and CrkL in diffuse intrinsic pontine glioma (DIPG) cell migration and invasion. In addition, Dr. Park is working to develop specific inhibitors of these proteins to block glioblastoma and DIPG cell migration and invasion.

In the lab, Dr. Park and his team take advantage of genetically engineered mouse models and the gene knockdown and overexpression technique to study tumorigenic functions of Crk and CrkL. They identified a protein that is activated by elevated Crk and CrkL and binds to Crk and CrkL. The new malignant connection promotes tumor cell migration and invasion. Dr. Park’s goal is to develop drugs that specifically break down the aberrant protein-protein complex between Crk and CrkL and their binding partners. To test the effects of chemical compounds on the binding of these proteins, Dr. Park developed in vitro assay systems and conducted a high-throughput screen. In partnership with the University of Kansas Cancer Center, the team has tested 200,000 chemical compounds and identified more than 600 potential candidate drugs. These compounds are undergoing rigorous post-screening validation using different biochemical experiments. They will continue to expand productive collaboration with KU core facilities to discover novel anticancer drugs. They are optimizing a new quadruple screening to discover inhibitors of both SH2 and SH3 domains of Crk and CrkL. The newly developed inhibitors will be used to advance studies of cancer and other human diseases in which Crk and CrkL play essential roles.

Dr. Park also collaborates with multiple core facility directors at the University of Kansas and the Univesity of Kansas Medical Center and has established a multidisciplinary research team for the structure-function relationship study. His team has developed Crk/CrkL-antagonist peptides that bind to the SH2 domains of Crk and CrkL and inhibit Crk/CrkL-mediated protein-protein interactions.

Previously, Dr. Park generated mutant mice lacking both Crk and CrkL in the developing brain and demonstrated that Crk and CrkL play essential overlapping functions in neuronal migration during brain development. Recently, genomic analysis of a patient with a severe global developmental delay and ataxia identified two new mutations in Crk and another protein that may interact with Crk. His team generated two mutant mouse strains harboring the two mutations and plan to study individual and combined contributions of the two genes to brain development. These phenotyping results will provide essential knowledge for understanding both the underlying mechanism of the clinical deficits and the signaling pathways in brain development, therefore laying the foundation for developing therapeutic interventions.