3D NKCC1 · Interdisciplinary approach to characterize the structure and the ion transport mechanism of NKCC1, a key target for brain disorders.
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2019-07-01 → 2021-06-30
- Финансиране от ЕС
- 168 370 €
- Участници
- 2
- Схема
- MSCA-IF-GF
Линиите свързват координатора с партньорите.
Накратко на български
Протеинът NKCC1 и начинът, по който транспортира хлорни йони в невроните, се анализират чрез 3D модели и взаимодействие с лекарства като буметанид. Това помага за разбирането на механизмите при мозъчни разстройства и търсенето на по-безопасни начини за тяхното лечение.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Interdisciplinary approach to characterize the structure and the ion transport mechanism of NKCC1, a key target for brain disorders.
The Cl importer NKCC1, together with the exporter KCC2, play a fundamental role in regulating the intracellular Cl concentration in neurons. The neurotransmitter GABA, through Cl-permeable GABAA receptors, is fundamental in physiological neurodevelopment. Defective GABAAergic transmission characterizes numerous brain disorders which affect an increasing range of individuals in Europe and worldwide, that still lack a pharmacological treatment. In this context, varying intracellular Cl concentration through the modulation of NKCC1 or KCC2 has demonstrated to be safer than direct receptor blockade. Importantly, the NKCC1/KCC2 expression ratio is defective in many brain diseases, and NKCC1 inhibition by the FDA-approved drug bumetanide rescues many symptoms in animal models. This has motivated clinical studies for the chronic usage of bumetanide in a broad range of brain disorders. However, bumetanide is a strong diuretic (due to inhibition of the kidney Cl-importer NKCC2), which makes it not suitable for chronic treatments in terms of drug compliance. Based on these premises, the overall objectives of the project are the structural characterization of NKCC1 (objective 1 - during year 1 of outgoing phase), and the functional characterization of NKCC1 (objective 2 – during year 2 of incoming phase). Using an interdisciplinary approach (structural biology, molecular biology, computational chemistry) the project investigated the structure-function relationship of NKCC1, which represents a breakthrough advance in understanding the ion binding and ion transport mechanisms. Further 3D characterization of NKCC1 also in presence of known ligands, such as bumetanide, will help in understanding the protein-ligand inhibition mechanism. In conclusion, the insights obtained from the multidisciplinary approach and the broad literature analysis that have been carried on helped us in investigating the binding sites of known drugs that modulate NKCC1 activity in order to treat brain disorders effectively and with fewer side effects. The present project will also accelerate the rational design and discovery of novel selective and potent NKCC1 inhibitors urgently needed in the treatment of brain disorders. These more specific drugs devoid the diuretic effect, associated with patient compliance in long-lasting cures.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Neurodevelopmental disorders affect millions of children in Europe and worldwide. A large body of literature indicates that inhibitory GABAergic transmission thorough Cl-permeable GABAA receptors is defective in many of these disorders. However, effective pharmaceutical treatments are still needed. There is increasing scientific evidence that varying the intracellular Cl concentration is one of the more physiological and effective ways to modulate GABAAergic transmission. This concentration is mainly established by the Cl importer NKCC1 and the Cl exporter KCC2. Importantly, the NKCC1/KCC2 ratio is defective in several brain disorders. Moreover, NKCC1 inhibition by the FDA-approved diuretic bumetanide rescues many symptoms in animal models. These findings have already led to clinical studies of bumetanide to treat a broad range of brain disorders. However, this requires chronic treatment, which poses serious issues for drug compliance, given the diuretic effect of bumetanide caused by the inhibition of the kidney-specific Cl transporter NKCC2. Crucially, these issues could be solved by selective NKCC1 inhibitors, which would have no diuretic effect. Yet there is still very little knowledge of the structure-function relationship of NKCC1 in terms of ion transportation and how bumetanide acts on NKCC1. The main goal of this fellowship is to resolve NKCC1’s structure using X-Ray crystallography and/or cryo-electron microscopy. This effort will be coupled to the functional characterization of NKCC1 using in vitro and in silico approaches. The fellow will thus integrate her research skills with key expertise in the structural and molecular biology of ion transporters, allowing her to grow into an independent group leader. Ultimately, this project will provide unprecedented insights into the structure-function relationships of NKCC1 in terms of ion transportation. This will critically accelerate the discovery of new and urgently needed drugs for brain disorders.
Оригинален текст от CORDIS (на английски).
Участници
- FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA · GenovaКоординаторИталия
- BAYLOR COLLEGE OF MEDICINE · Houston TxСъединени щати
Връзки
Данни: CORDIS, © Европейски съюз