Jianmin Cui<\/a>, a professor of biomedical engineering in the McKelvey School of Engineering at Washington University in St. Louis, plans to develop precision medicine for channelopathies in the KCNMA1 BK potassium ion channel with a five-year $3 million grant from the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health (NIH). Cui\u2019s collaborators include Huanghe Yang, an associate professor of biochemistry, of neurobiology and of medicine at Duke University who earned master\u2019s and doctoral degrees in biomedical engineering from WashU; and Xiaoqin Zou, Curators\u2019 Distinguished Professor at the University of Missouri.<\/p>\nPrior to 2005, researchers knew genetic mutations in potassium ion channels led to epilepsy and heart arrhythmias such as Long QT syndrome. In 2005, new research showed that mutations in a gene in the BK potassium ion channel led to a variety of severe neurodevelopmental disorders, cognitive impairments and movement disorders. These disorders manifest differently in nearly every patient, creating a challenge for caregivers and clinicians.<\/p>\n
Since researchers found the first channelopathy in KCNMA1, more than 40 new variants associated with neurological disorders have been reported. And in the past year, researchers have found nearly 80 new variants. However, the mutations can occur in many different locations of the ion channel structure, causing a wide range of symptoms, from intellectual and developmental disabilities to ataxia and dystonia.<\/p>\n
\u201cSome of these mutations increase the channel activity,\u201d Cui said. \u201cThese mutations will make the channel work better in certain circumstances. But some of them are loss of function, which have different symptoms, but can also overlap. We don\u2019t know why the increase or loss of function would cause different symptoms and affect the cells and brain in different ways.\u201d<\/p>\n
With the federal funding, Cui and his collaborators plan to study how the mutations affect the molecular mechanism of BK channel activation to understand if the mutation affects the voltage-dependent activation, the calcium-dependent activation or another more intrinsic activation of the channel.<\/p>\n
\u201cWe want to find those things to develop a strategy for different patients,\u201d Cui said. \u201cFor example, if this channel is affected in intrinsic opening to cause certain diseases, then we try to use a strategy of drug screening that directly targets that intrinsic opening so that it can hopefully correct the symptoms for that particular kind of patient effectively without damaging the total function of the channel.\u201d<\/p>\n
Using electrophysiology, Cui\u2019s lab will identify the molecular mechanisms of the channel and how the mutations change the channel function that lead to disease or disorder. The lab also will look to find the location of the mutation in the channel, which helps to pinpoint the exact target for potential drug development. Zou\u2019s computational lab at the University of Missouri will perform docking, which places thousands of chemicals onto those locations of the ion channel identified by Cui\u2019s lab to determine if one or more will bind there and ultimately change the channel function and the molecular mechanism. Yang\u2019s lab at Duke will create mouse models of the channel mutations and test the compounds to determine their effectiveness on symptoms.<\/p>\n
\u201cThere is no particular drug that is effective in treating this,\u201d Cui said. \u201cThere are drugs that treat some of the symptoms, such as anti-seizure drugs, but we want to find a drug specific to the specific mutations to treat patients more effectively without a high dosage, which can often cause other problems.\u201d<\/p>\n
Cui and his collaborators are motivated in their work by the families and caregivers of those with these debilitating disorders.<\/p>\n
\u201cWhile these diseases are uncommon, for those affected, it\u2019s very, very bad and just destroys the life of the patient, and to a certain extent, the family,\u201d he said. \u201cIt is very important to try to find a cure. There may be a genetic component to this, and there may be drugs that could help. It\u2019s a step in the right direction.\u201d<\/p>\n
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