Specific K+ channel modulation offers an enormous potential for the development of new drugs. One channel that constitutes an especially promising therapeutic target is the voltage-gated Kv1.3 channel. Homomeric Kv1.3 channels are found in T and B lymphocytes and their expression is up-regulated in terminally differentiated effecter memory T (TEw) cells and class-switched memory B cells suggesting that Kv1.3 blockers should be useful for the treatment of autoimmune diseases such as multiple sclerosis, type-1 diabetes, psoriasis, contact dermatitis, rheumatoid arthritis and myasthenia gravis. This concept has been validated by the demonstration that autoreactive T cells from patients with multiple sclerosis and type-1 diabetes are predominantly Kv1.3-high TEM cells and that the Kv1.3 blocking peptide ShK can treat an animal model of multiple sclerosis. However, despite Kv1.3's obvious therapeutic importance, the pharmaceutical industry has so far been unsuccessful in developing selective and potent small molecule Kv1.3 blockers. With the alkoxypsoralen PAP-1 my laboratory recently identified the first small molecule inhibitor of Kv1.3 that blocks the channel with an EC50 of 2 nM and displays selectivity over the cardiac potassium channel Kv1.5. PAP-1 does not exhibit cytotoxic or phototoxic effects, is negative in the Ames test, potently inhibits the proliferation of human TEM cells and suppresses delayed type hypersensitivity (DTH), a TEM cell mediated reaction, in rats when administered intraperitoneally or orally. PAP-1 therefore seems to constitute an excellent new tool to further explore Kv1.3 as a target for immunosuppression and could potentially be developed into orally available immunomodulator. We the help of this proposal we intend to thoroughly explore the therapeutic potential of PAP-1.
Under Aim -1 we will determine PAP-1's pharmacokinetics and test which effect long-term suppression of memory cells with PAP-1 has on the immune system.
Under Aim 2 we will test whether PAP-1 treats allergic contact dermatitis, an animal model for CD8+ T cell mediated skin reactions like psoriasis, and experimental autoimmune myasthenia gravis, a model for the T-cell dependent antibody-mediated autoimmune disease myasthenia gravis. Since TEM cells also play an important role in early and late-stage transplant rejection we will further test whether PAP-1 can suppress acute and chronic rejection in a rat kidney transplant model (Aim 3). Lay: Potassium channels are proteins that tunnel the cell membrane and conduct potassium ions. One of these channels, called Kv1.3, is expressed in white blood cells and has been proposed as a potential new therapeutic target for the treatment of autoimmune diseases.
The aims of our proposal are to test a Kv1.3 blocker that we designed in animal models of autoimmune diseases and transplant rejection. ? ? ?
|Grimaldi, A; D'Alessandro, G; Golia, M T et al. (2016) KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages. Cell Death Dis 7:e2174|
|Chen, Yi-Je; Nguyen, Hai M; Maezawa, Izumi et al. (2016) The potassium channel KCa3.1 constitutes a pharmacological target for neuroinflammation associated with ischemia/reperfusion stroke. J Cereb Blood Flow Metab 36:2146-2161|
|D'Alessandro, Giuseppina; Grimaldi, Alfonso; Chece, Giuseppina et al. (2016) KCa3.1 channel inhibition sensitizes malignant gliomas to temozolomide treatment. Oncotarget 7:30781-96|
|Roach, Katy M; Feghali-Bostwick, Carol; Wulff, Heike et al. (2015) Human lung myofibroblast TGF?1-dependent Smad2/3 signalling is Ca(2+)-dependent and regulated by KCa3.1 K(+) channels. Fibrogenesis Tissue Repair 8:5|
|Chen, Yi-Je; Wallace, Breanna K; Yuen, Natalie et al. (2015) Blood-brain barrier KCa3.1 channels: evidence for a role in brain Na uptake and edema in ischemic stroke. Stroke 46:237-44|
|Hong, Liang; Singh, Vikrant; Wulff, Heike et al. (2015) Interrogation of the intersubunit interface of the open Hv1 proton channel with a probe of allosteric coupling. Sci Rep 5:14077|
|Jin, Lee-Way; Horiuchi, Makoto; Wulff, Heike et al. (2015) Dysregulation of glutamine transporter SNAT1 in Rett syndrome microglia: a mechanism for mitochondrial dysfunction and neurotoxicity. J Neurosci 35:2516-29|
|Feske, Stefan; Wulff, Heike; Skolnik, Edward Y (2015) Ion channels in innate and adaptive immunity. Annu Rev Immunol 33:291-353|
|Koch Hansen, Lars; Sevelsted-Møller, Linda; Rabjerg, Maj et al. (2014) Expression of T-cell KV1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis. J Crohns Colitis 8:1378-91|
|Roach, Katy M; Wulff, Heike; Feghali-Bostwick, Carol et al. (2014) Increased constitutive ?SMA and Smad2/3 expression in idiopathic pulmonary fibrosis myofibroblasts is KCa3.1-dependent. Respir Res 15:155|
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