STrkB · The structural biology of TrkB-BDNF signalling
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2017-07-01 → 2019-06-30
- Финансиране от ЕС
- 183 455 €
- Участници
- 2
- Схема
- MSCA-IF-EF-ST
Линиите свързват координатора с партньорите.
Накратко на български
Молекулярната структура на взаимодействието между протеина BDNF и рецептора TrkB определя как се предават сигналите в мозъка. Разбирането на този механизъм помага за разработването на нови терапии при невродегенеративни заболявания като Алцхаймер и Паркинсон.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
The structural biology of TrkB-BDNF signalling
The molecular events underlying the formation and function of neuronal circuits during brain development are strictly coordinated and controlled. Neurotrophin family factors are important players in this process and act primarily through interactions with tropomyosin-related kinase (Trk) receptors, promoting neuronal survival and synaptogenesis. Furthermore, the mature brain is not a “static” organ, undergoing constant morphological and functional changes at the level of neuronal synapses. Among the major neurotrophins, the brain-derived neurotrophic factor (BDNF) molecules act by binding to the TrkB receptor, a type-I membrane protein. This leads to TrkB dimerization, auto-phosphorylation and initiates downstream signalling events. However, the molecular architecture of this complex and the mechanism of signal propagation across the plasma membrane remained unknown. BDNF expression levels in the brain are diminished in neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases. It is proposed that onset of disease occurs before the characteristic morphological changes readily observable in the brain, starting at the level of synaptic dysfunction. Therefore, future approaches for the treatment of neurodegenerative diseases are proposed to include “synaptic repair”, which targets pathophysiology before pathogenesis. Due to its functions, therapies exploiting the use of BDNF and functional mimetics have been proposed, yet clinical trials performed to date led to inconclusive results due to its lack of stability and solubility. To understanding the mechanism of BDNF-dependent TrkB signalling, and provide a platform for novel therapies targeting this pathway, the overall objective of this project was to define in structural and mechanistic terms the steps leading to TrkB activation upon BDNF binding. Using a combination of X-ray crystallography, single-particle cryo-electron microscopy and complementary biophysical techniques, this project provided the first insights into the organization of the BDNF-TrkB complex in the extracellular region.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Neuronal circuit development involves multiple stages that are regulated by neurotrophic factors. One of the key players, the brain-derived neurotrophic factor (BDNF), is involved in the development and functional modulation of circuits by promoting neuronal survival, synaptogenesis, synaptic transmission and synaptic plasticity. BDNF acts by binding to the tropomyosin-related kinase receptor B (TrkB), a type-I membrane protein, to trigger downstream signaling. However, the molecular architecture of this complex and the mechanism of signal propagation across the membrane remain unknownThe key aim of this project is to define in structural and mechanistic terms the steps leading to TrkB activation upon BDNF binding. I will use X-ray crystallography to determine the structure of the extracellular TrkB-BDNF complex, and validate this model by mutagenesis and biophysical techniques. Single particle cryo-electron microscopy will be used to solve the full-length TrkB-BDNF complex structure. To validate and relate these structures to signaling, structure-based hypotheses will be tested in live cells by fluorescence imaging.Furthermore, to exploit the structural information gained above, I will engineer BDNF molecules with improved physico-chemical properties as well as generate nanobodies against the TrkB extracellular region. These will be screened by biophysical, structural and cellular approaches to evaluate their (i) binding mode and affinity and (ii) ability of promote TrkB activation. Subsequently, collaborative studies in mouse models will test whether these molecules behave as efficient BDNF mimetics in vivo.This multidisciplinary approach will enable me to define determinants of the TrkB-BDNF complex formation, its activation mechanism, and to use this information towards providing a platform for the design of novel tools that target and modulate this crucial signaling pathway, to promote synaptic repair and functional recovery in damaged neuronal circuits.
Оригинален текст от CORDIS (на английски).
Участници
- UNITED KINGDOM RESEARCH AND INNOVATION · SWINDONКоординаторОбединеното кралство
- THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OxfordОбединеното кралство
Връзки
Данни: CORDIS, © Европейски съюз