Wulff, Heike - University of California, Davis

研究领域

Potassium channel modulators for the treatment of autoimmune and cardiovascular disease. Research Synopsis My laboratory focuses on the design of new potassium channel modulators as research tools and as potential drugs. We are particularly interested in the voltage-gated Kv1.3 and the calcium-activated KCa3.1 channels in immune cells and in the calcium-activated KCa2/3 channels in the cardiovascular and nervous system. In human T and B lymphocytes Kv1.3 and KCa3.1 are critically involved in regulation of membrane potential, calcium signaling, proliferation and cytokine secretion. Expression of these two channels changes dramatically as T and B cells differentiate from naïve into memory cells, allowing the selective targeting of memory T and B cells with Kv1.3 blocking compounds. We further demonstrated that Kv1.3 is over-expressed on autoreactive T cells in the blood from patients with multiple sclerosis (MS) and type-1 diabetes as well as in the infiltrating T cells in active MS brain lesions. Kv1.3 is therefore regarded as a promising target for the treatment of memory T cell mediated autoimmune diseases such as multiple sclerosis, type-1 diabetes and psoriasis. Through a combination of synthetic medicinal chemistry and electrophysiology we have successfully developed selective small molecule blockers for both KCa3.1 and Kv1.3 and are currently evaluating these in various animal models of autoimmune disease and transplant rejection. For example, our small molecule Kv1.3 blocker PAP-1 suppresses allergic contact dermatitis and prevents type-1 diabetes in rats, while our KCa3.1 blocker TRAM-34 can prevent restenosis in rats and pigs and atheriosclerosis in mice. Another project in my laboratory is the design of activators of small- and intermediate-conductance calcium-activated potassium channel modulators as potential therapeutics for the treatment of ataxia, epilepsy and hypertension.

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Wulff H., Calabresi, P.A., Allie R., Yun S., Pennington M., Beeton C., Chandy K.G. (2003) The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS. Journal of Clinical Investigation 111:1703-1713. Schmitz A., Sankaranarayanan A., Azam P., Schmidt-Lassen K., Homerick D., Hansel W., Wulff H. (2005) Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory T cells in autoimmune diseases. Beeton C., Wulff H.* (*Co-senior authors), Standifer N.E., Azam P., Mullen K.M., Pennington M.W., Kolski-Andreaco A., Wei E., Grino A., Counts D.R., Wang P., LeeHealey C.J., Andrews B., Sankaranarayanan A., Homerick D., Roeck W.W., Tehranzadeh J., Stanhope K.L., Zimin P., Havel P.J., Griffey S., Knaus H.-G., Nepom G.T., Gutman G.A., Calabresi P.A., Chandy K.G.* (2006) Kv1.3 channels: therapeutic target for T cell-mediated autoimmune diseases. Proceedings of the National Academy of Sciences USA 103:17414-17419. Wulff H., Zhorov B.S. (2008) K+ Channel Modulators for the Treatment of Neurological Disorders and Autoimmune Diseases. Chemical Reviews 108:1744-1573. Sankaranarayanan A., Raman G., Zimin P.I., Hoyer J., Köhler R., Wulff H. (2009) Naphtho[1,2-d]thiazol-2-ylamine (SKA-31), a new activator of KCa2 and KCa3.1 potassium channels, potentiates the endothelium-derived hyperpolarizing factor response and lowers blood pressure. Molecular Pharmacology 75:281-295. Brähler S., Kaistha A.., Schmidt V.J., Wölfle S.E., Busch C., Kaistha B.P., Kacik M., Hasenau A.-L., Grgic I., Si H., Bond C.T., Adelman J.P., Wulff H., Wit C., Hoyer J., Köhler R. (2009) Genetic deficit of SK3 and IK1 channels disrupts the EDHF vasodilator pathway and causes hypertension. 119:2323-2332. Grgic I., Kloss M., Kiss E., Sautter J., Kaistha A., Müller A., Kaistha B.P., Timphus E.M., Raman G., Wulff H., Strutz F, Gröne H.-J., Köhler R., Hoyer J. (2009) Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels. Proceedings of the National Academy of Sciences Wulff H., Castle N., Pardo L. (2009) Therapeutic potential of modulation of voltage-gated potassium channels. Nature Reviews Drug Discovery 8:982-1001.