The primary interest of our laboratory is to elucidate molecular mechanisms of signal transduction and telomerase regulation and to determine their roles in the development and treatment of cancer and Alzheimer’s disease.  Specifically, we have recently discovered Pin1-catalyzed conformational regulation after phosphorylation as a novel signaling mechanism with the major but opposite impact on cancer and Alzheimer’s disease, as well as identified the telomere protein Pin2/TRF1 and the telomerase inhibitor PinX1, which are important for cancer and aging.

Unlike phosphorylation or dephosphorylation, nothing is gained or lost during Pin1-catalyzed cis-trans proline isomerization after phosphorylation and no tool was available to inhibit Pin1 or detect isomerization. To take on these challenges, we have developed a mechanism-based high throughput screen and identified several small molecule Pin1 inhibitors, including all-trans retinoic acid that has promising property to simultaneously block multiple cancer pathways in leukemia, breast and liver cancer.  We have also developed innovative peptide chemistry to create antibodies able to distinguish cis from trans Pin1 substrate proteins. These new generation of antibodies led us to discover that cis P-tau is a common early disease driver that may cause and spread progressive neurodegeneration in Alzheimer’s disease, traumatic brain injury and chronic traumatic encephalopathy (CTE), but can be effectively blocked by cis P-tau antibody. Our current focus is to further optimize our Pin1 inhibitors to block multiple cancer pathways and inhibit cancer stem cells and to further develop conformation-specific antibodies for diagnosis and treatment of Pin1-related diseases including cancer, Alzheimer’s, disease, traumatic brain injury and CTE.