Kun Ping Lu, M.D., Ph.D.

 

Professor of Medicine

Beth Israel Deaconess Medical Center
Center for Life Science, Room 0408
3 Blackfan Circle
Boston, MA 02115
Tel: 617-735-2016
Fax: 617-735-2050
Email: klu@bidmc.harvard.edu
Visit my lab page here.




Our primary research interest is to elucidate the role and regulation of Pro-directed phosphorylation signaling in physiology and disease. Our discovery of the phosphorylation-specific prolyl isomerase Pin1 led us to identify a novel postphosphorylation signaling mechanism, where prolyl isomerization catalytically induces conformational changes after hosphorylation to regulate the function of proteins in cell signaling. Our laboratory has further shown that Pin1 function is tightly regulated under physiological conditions and its deregulation plays a pivotal role in the pathogenesis of certain human diseases, notably cancer and Alzheimer’s disease.

Pin1 is prevalently overexpressed in human cancers and functions as a novel catalyst essential for numerous oncogenic pathways. Consequently, Pin1 inhibition suppresses cancer development, whereas Pin1 overexpression leads to genomic instability and cancer development. We have developed potent Pin1 inhibitors that have the unique attractive property to inhibit number cancer-driving pathways.

In Alzheimer’s disease, Pin1 activity is critical for controlling tau hyperphosphorylation and Abeta overproduction, but is inhibited in the diseased brain. Pin1 is the first gene whose deletion is sufficient to cause tau hyperphosphorylation, tangle formation, Abeta overproduction and neurodegeneration in an age-dependent manner. Thus, Pin1 is pivotal in protecting against age-dependent neurodegeneration, providing new insight into the pathogenesis and treatment of Alzheimer’s disease.

We have developed novel peptide chemistry to generate first antibodies. specifically recognizing cis and trans pSer/Thr-Pro motifs to demonstrate the conformation-specific function and regulation under physiological and pathological conditions. For example, cis, but not trans, p-tau is early pathogenic in the development in Alzheimer’s disease and Pin1 protects against neurodegeneration by converting cis to the non-pathological trans. These findings provide the first generally applicable in vivo approach to study conformational regulation after phosphorylation signaling and suggest novel conformation-specific antibodies and vaccines, which we are developing for the diagnosis and treatment of Alzheimer’s and other diseases.


For a complete listing of publications click here.



Last Update: 10/30/2013