H2020Индивидуална стипендия2018–2020

TNFaLysMyr · Unique TNFα lysine myristoylation; elucidating its function, regulation and integration into inflammation

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

Период: 2018-09-01 → 2020-08-31
Финансиране от ЕС: 183 455 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Протеинът TNFα и специфичната му модификация чрез прикрепяне на мастна киселина (миристоилиране) се анализират чрез химическа биология и биохимия. Разбирането на този процес помага за подобряване на терапиите при автоимунни заболявания, рак и сепсис.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Unique TNFα lysine myristoylation; elucidating its function, regulation and integration into inflammation

Tumour Necrosis Factor-α (TNFα) is a pro-inflammatory cytokine with major roles in immunity and cellular homeostasis. Deregulated TNFα signalling is implicated in many autoimmune and inflammatory diseases, including sepsis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type I diabetes and cancer. Blocking TNFα signalling with antibody drugs is a successful treatment strategy but has only temporary effects and clinical responses vary in different diseases, owing to the complexity of TNFα signalling. To improve and expand therapeutic strategies, a better understanding of TNFα and the many other cytokines secreted from cells, is crucial. It was very recently shown that TNFα is myristoylated on a strictly conserved lysine residue (KMyr) – a unique post-translational modification – suggesting an important but yet unexplored role for lysine myristoylation in cytokine biology. The aim of the project is to investigate the impact of KMyr on TNFα signalling, and its wider role in secretion and signalling of other cytokines, using a unique multi-disciplinary approach combining state-of-the-art chemical biology tools complemented with molecular cell biology, proteomics and biochemistry.

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

Цел на проекта

Tumour Necrosis Factor-alpha (TNFa) is an important cytokine implicated in many autoimmune and inflammatory disorders, in which TNFa-blocking antibody drugs have become first line treatment. Nevertheless, clinical responses are variable. To improve and expand therapeutic strategies, a better understanding of TNFa and the many other cytokines secreted from cells is crucial. It was recently shown that TNFa is myristoylated on a lysine residue (KMyr), a unique modification that suggests an important but yet unexplored role for KMyr in cytokine biology. I will investigate the impact of KMyr on TNFa signalling, and its wider role in secretion and signalling of other cytokines, using a unique multi-disciplinary approach combining state-of-the-art chemical biology tools with molecular cell biology and proteomics. The role of KMyr in TNFa trafficking, secretion and signalling will be identified using human macrophage cell lines that produce mutant TNFa proteins with the relevant lysine residue substituted or deleted. KMyr proteins will be identified through a powerful approach that introduces a small chemical tag into the myristate in cells; this tag can be selectively functionalized to allow sensitive fluorescence imaging of KMyr within living cells, and purification for identification by mass spectrometry. The global scope of KMyr in the proteome will be analyzed in parallel, with emphasis on other secreted cytokines such as IL1alpha, which may be controlled too via KMyr. Regulation of TNF KMyr will be explored by identifying KMyr transferases and demyristoylases using chemical photo-affinity tools that can bind proteins interacting with KMyr, yielding putative targets for future first line therapies.

Оригинален текст от CORDIS (на английски).

Участници

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE · LondonКоординаторОбединеното кралство