Research

Thesis title: "Potassium Kv10.1 Channel-Lipid Dysregulation in Diseases"

Thesis outline: Potassium channels are one of the largest families of transmembrane proteins that enable K+ ions flux across cell membranes through highly selective pores. KV channels are the largest family among potassium channels and include 12 subfamilies, named Kv1 to Kv12. Among these, Kv10.1, also known as Eag1, belongs to the ether-à-go-go family, alongside Kv11 (erg, eag-related gene) and Kv12 (elk, eag-like K+ channel). Recent research revealed that Kv10.1 is an important biomarker and a potential therapeutic target in cancer treatment. Notably, Kv10.1 over-expression has been detected in over 75% of human cancers, including breast, lung, and ovarian malignancies, among others. The channel was demonstrated to play an important role in multiple processes of cancer biology, including cell proliferation, migration, angiogenesis, survival, and metabolic remodeling. In vitro and in vivo studies have also revealed that suppressing Kv10.1 expression using siRNA or inhibiting its pharmacological activity with small molecules such as imipramine or astemizole significantly reduces the proliferation and metastasis of cancer cells.

Until now, several studies have focused on identifying potential compounds that inhibit Kv10.1 as promising cancer treatments and have yielded encouraging initial results. However, the development of Kv10.1-targeting drugs faces significant challenges, primarily due to their non-selective inhibition of other ion channels, particularly Kv11.1 (hERG). hERG plays an important role in cardiovascular function, and its inhibition can lead to severe cardiac risks, including potentially life-threatening arrhythmia. Due to the structural similarity between Kv10.1 and Kv11.1 (50% sequence identity), most Kv10.1 inhibitors also inhibit Kv11.1, with some compounds showing even higher affinity for Kv11.1 than Kv10.1. Therefore, it is necessary to identify compounds that selectively target Kv10.1 while minimally affecting other ion channels such as Kv11.1. One of the promising solutions to this challenging problem is identifying novel druggable sites unique to Kv10.1.

Recent studies have shown that lipids play an important role in regulating the structure and activity of all ion channels, including potassium channels, which are embedded in the cell membrane's complex lipid environment. Lipid regulation can occur through two primary mechanisms: direct binding to the ion channel as a ligand at active or allosteric sites, or indirectly through alterations in membrane properties. Recently, research has demonstrated significant alterations in cell membrane lipid composition under pathological conditions such as various forms of cancer and Alzheimer's disease compared to normal physiological states. Therefore, in this study, we aim to examine the influence of lipid composition on Kv10.1 function in physiological brain plasma membranes and some disease models with documented lipid composition changes.

Funding: Ernst Mach Grant

Supervisor: Anna Weinzinger

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