Research Focus

The laboratory studies the mechanisms of inter- and intracellular signal transduction and its main goal is to elucidate the functional properties of molecular components involved in the complex regulation of secretion, excitation-contraction coupling, cell proliferation, and apoptosis. All research projects are guided by our desire to understand the relevant clinical context in which the molecular mechanisms operate, whether human disease states are causally linked or impacted, and ultimately how these mechanisms can be modified pharmacologically or genetically to treat patients. Our research primarily concentrates on four clinical areas: immune disorders (autoimmune diseases, allergy, inflammation), metabolic disorders (diabetes), anoxic disorders (stroke), and oncologic disorders (various cancers).

The approach to study signaling events is mainly at the single-cell level and employs a variety of biophysical techniques (e.g., electrophysiology and digital imaging) to assess important parameters such as ionic fluxes, membrane potential, intracellular second-messenger and calcium levels. These techniques are complemented by pharmacological, biochemical, molecular biological, and genetical tools to investigate signaling pathways in native systems (cell lines, primary and tissue cultures), in genetically modified systems (transient and/or stable transfections of cells), and in cells derived from transgenic animals. A further research focus involves drug discovery efforts using high-throughput screening aimed at developing experimental therapeutics and translational studies in defined animal models and clinical trials in humans.

Autoimmune Disease: We have discovered that the anti-bacterial drug clofazimine also acts as an immunosuppressant in memory T lymphocytes by virtue of inhibiting the potassium ion channel Kv1.3. This work forms the basis for a translational research project in which we investigate the clinical potential of clofazimine in the treatment of autoimmune diseases such as multiple sclerosis, psoriasis, diabetes type 1, and rheumatoid arthritis.

Cancer: We have identified and characterized several novel ion channels, including CRAC, TRPM2, TRPM4 and TRPM7. Several of these ion channels are linked to cell growth and proliferation of cancer cells and we are presently exploring the therapeutic potential of several novel pharmacological tools specifically directed towards these channels. Calcium ions play an important role as second messengers in regulating a plethora of physiological and pathological processes, including the progression of cancer. Several selective and non-selective Ca2+-permeable ion channels are implicated in mediating Ca2+ signaling in cancer cells, including store-operated calcium entry (SOCE). We have identified transient receptor potential ion channels that, when activated, lead to calcium influx and cell death in multiple myeloma.

Natural Products Drug Discovery: We are developing functional bioassays against various ion channels and have screened chemical and natural product libraries for pharmacological activity. This identified waixenicin A, a molecule produced by a Hawaiian soft coral, as a potent and selective inhibitor of TRPM7 that suppresses the growth of tumor cells. Around 200–400 million people in South and Southeast Asia and the Asian Pacific Region and about 600 million world-wide are addicted to areca. Areca use is associated with a high prevalence of oral carcinoma, oral pre-cancerous lesions, oral submucous fibrosis, as well as periodontal and inflammatory diseases. We have identified active chemical components of Areca that mediate calcium signals in immunocytes and determined the molecular mechanisms by which calcium is mobilized in these cells. Chronic pain – often arising from cancer, musculoskeletal injury, neurological dysfunction, or autoimmune disorders – affects ~100 million Americans with associated economic costs of $500 billion annually. Overreliance on opioid analgesics to treat pain has resulted in a public health crisis, where opioid overdoses are predicted to claim more than 100,000 lives in 2021 and are now, aside from COVID-19, the leading cause of avoidable deaths in the nation. We have assembled a complementary and interdisciplinary team that combines expertises in molecular and cellular signaling, ion channel biology, natural products chemistry, and molecular pharmacology as well as all aspects of endocannabinoid biology together with Ken Mackie, University of Indiana. Our high-throughput (HTS) bioassays have identified several cannabinoids that inhibit calcium signaling in immune cells and offer therapeutic potential for treating pain, autoimmune disease, and cancer.