Research | Diagnostics & Therapeutics

Small molecule modulators for CRAC channel

The genetic basis of defective CRAC channel function in human SCID patients with inherited severe combined immunodeficiency has been traced back in loss-of-function mutations in either ORAI1 or STIM.  Although both ORAI1 and STIM1 are widely expressed in different tissues, the major clinical consequences of defective CRAC channels are surprisingly limited to the immune system, skeletal muscle and ectodermally derived tissues. Similar phenotypes were recapitulated in mice with targeted disruptions of the Stim1, Stim2 and Orai1 genes.  Thus, small molecule inhibitors that specifically target the STIM-ORAI pathway have a high potential to suppress immune function selectively and may lack the toxicity of current immunosuppressive agents, such as cyclosporine A and FK506.  We will examine the therapeutic values of specific small molecule inhibitors of the SOC channels in the treatment of autoimmune diseases.  

In addition, abnormal SOCE is known to induce a higher rate of focal adhesion turnover and increased migration of metastatic cancer cells.  This adverse effect can be effectively attenuated by knockdown of ORAI1/STIM1. When targeted to tumor cells in the form of antibody-drug conjugates, SOC inhibitors may find their broad use in attenuating tumor growth, migration and metastasis


Use iPS cells technology to investigate ion channelopathies

The long-term goal in this endeavor is to create human models of cardiovascular and neurological channelopathies by generating iPS cell-derived cardiac or neuronal cells from fibroblasts from patients, to establish pharmacology profiles of known drugs used to treat each model, as well as to uncover drugs that may be of therapeutic value in treating these disorders. These cells also have the potential to be used in regenerative therapy, to restore function to damaged or failing organs without fear of autoimmune rejection. At the initial stage,  we will focus on patients with Brugada syndrome, a genetic disease that is characterized by abnormal electrocardiogram (ECG) recordings with typical ST segment elevation in the anterior precordial leads V1-V3 and an increased risk of sudden death due to ventricular fibrillation in heart.