| DISCOVERY |
Rationale: Calcium signaling, store-operated channels and inflammation One of the most powerful effector mechanisms of the immune system is the reaction initiated by IgE-dependent stimulation of tissue mast cells and their circulating counterparts, basophils. Calcium ions also play a central role in the process of activation of these cells. All mast cells are derived from bone marrow progenitors, and mature cells are found throughout the body, predominantly located near blood vessels, nerves, and beneath epithelia. In humans, the factors that regulate mast cell growth and development are not as well defined. Mast cells and basophils are activated by cross-linking of FcåRI molecules, which occurs by binding of multivalent antigens to the attached IgE molecules. Activation of mast cells and basophils results in three types of calcium-regulated responses: secretion of the granule contents via exocytosis, synthesis and secretion of lipid mediators, and cytokines. Although there is some evidence suggesting the existence of voltage-operated calcium (Ca++) channels in T lymphocytes, several lines of evidence strongly support the idea that store-operated calcium channels are solely responsible for Ca++ influx during T cell activation. First, the Ca++ currents induced by T cell receptor (TCR) cross-linking and by passive store depletion are identical in terms of ion selectivity, conductance, Ca++-dependent inactivation, and blockade by heavy metals. Second, stimulation of the TCR with lectins or antibodies does not further increase Ca++ influx in those T cells which stores are already depleted with thapsigargin. Finally, in patients with a severe immunodeficiency, nonresponsive T cells displayed a specific defect in Ca++ influx associated with the absence of calcium release-activated current (ICRAC). A similar situation might occur in mast cells and other leukocytes. For example, platelet activating factor-mediated Ca++ influx in human neutrophils is primarily attributed to store-operated mechanisms. MediciNova has conducted high throughput screening of a library of compounds (over 25,000 compounds) for SOC-specific inhibitors, and conducted medicinal chemistry work to optimize the identified leads. |
| COMPANY | MediciNova |
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