H2020Индивидуална стипендия2015–2017

MaSCheNav · Mass Spectrometry-Based Chemoproteomic Profiling of Nav1.7, a Voltage-Gated Sodium Channel

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2015-11-01 → 2017-10-31
Финансиране от ЕС: 183 455 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Връзката между липидите и протеините се анализира чрез комуникацията между раковите клетки и околната гидратирана тъкан. Разбирането на тези процеси помага за разработването на нови методи за терапия срещу рака.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Mass Spectrometry-Based Chemoproteomic Profiling of Nav1.7, a Voltage-Gated Sodium Channel

(The project described in this report has been subjected to an amendment, approved by the EU commission, due to the unexpected closure of the industrial research unit involved as a partner organisation in the original application.) The project focussed on the interaction between protein lipidation and cancer, looking in particular at the role of cancer/stroma communication in a hetero-cellular environment. Cancer is known for having an altered lipid metabolism, due to cancer cells’ markedly increased need for lipids, to support their growth. Moreover, de novo lipogenesis occurs downstream of various common oncogenic events. Protein lipidation is a unique modification enabling protein interaction with membranes. This modification is thus involved in vesicular trafficking and signalling and is crucial for cellular communication, which plays a major role in cancer. In particular, cancer-stroma hetero-cellular signalling is fundamental in supporting tumour growth. The stroma secretes growth factors and cytokines and deposit extracellular matrix, leading to an increased growth of fibrous tissue. The latter, in turn, implies reduced perfusion, thus potentially contributing to therapeutic resistance in many cancers, and constituting an interesting pharmacological target for combination therapy. Therefore, the altered lipid scenario in cancer could affect protein lipidation, which in turn plays a crucial role in many signalling events driving cellular communication in the tumour microenvironment. Understanding this complex interplay will help us advance in the development of novel therapeutics to tackle cancer in a more comprehensive way.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Chronic pain represents a major unmet medical need which has been linked to changes in voltage-gated sodium channels (VGSCs). These channels are transmembrane protein-complexes with a key-role in signal transmission in excitable cells, such as neurons, and allow the flux of Na+ ions through the cellular membrane in response to specific stimuli, thus controlling the generation and propagation of action potentials. Nine VGSC subtypes are known to be expressed in different cell types, and among them subtype Nav1.7 is of extreme interest since it is involved in nociceptive processing (pain-sensing) in the peripheral nervous system. Remarkably, patients suffering from congenital indifference to pain syndrome, which derives from loss-of-function mutations of the gene encoding for Nav1.7, have a dramatically reduced ability to perceive painful stimuli, but are otherwise perfectly healthy. Therefore, Nav1.7 has been recognized as an exciting target for pharmacological treatments of pain. However, detailed structural and functional information is lacking, and its attainment represents a fundamental step in the challenging task of finding Nav subtype-selective modulators. Thus, the main focus of my project is to study ligand-binding events with known modulators, thereby paving the way to the design of safe and selective inhibitors. I will develop, by solid phase peptide synthesis, a chemical probe specifically designed to isolate Nav1.7, using a tandem photoaffinity labeling-bioorthogonal conjugation approach. This probe will be applied in model cell lines expressing the channel, in order to study their binding interaction through mass spectrometry-based chemoproteomics. Once these chemical tools are established and validated in the model system, I will translate them to patient-derived cells, in order to study disease-relevant systems.

Оригинален текст от CORDIS (на английски).

Участници

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE · LondonКоординаторОбединеното кралство