SubsidieMeestersIn situ structural biology of human immune defence
Developing super-resolution cryo-correlative light and electron microscopy (SRcryoCLEM) to enhance in situ structural biology for antibody-mediated immunity and therapeutic advancements.
Projectdetails
Introduction
Structural biology provides insights into protein function but generally requires purified complexes, which necessitates removing the protein from its native context. We therefore lose in situ information. Cryo-electron tomography (cryoET) provides this information, but finding a specific protein in a cell is akin to searching for a needle in a haystack 50 m tall.
We are at the forefront of developing a technique to solve this problem; by combining super-resolution (SR) light microscopy on samples prepared for cryoET, we can locate specific proteins and events within whole mammalian cells. This information can be correlated with 3D cryoET volumes to perform in situ structural biology. We call this technique super-resolution cryo-correlative light and electron microscopy (SRcryoCLEM). Here, I describe how we will enhance SRcryoCLEM and use it to image antibody-activated aspects of human immunity, enabling the development of cutting-edge immunotherapeutics.
Aim 1: Augmenting SRcryoCLEM
The first aim of this proposal is to augment SRcryoCLEM with multicolour imaging and automated data analysis.
- Spectrally-distinct fluorescent proteins will be identified that are ideal for cryoSR imaging.
- AI-based volume segmentation and automated particle picking will help to democratize in situ structural biology.
Aim 2: Delivering In Situ Structural Data
The second aim is to deliver in situ structural data to explain discrepancies in antibody effector functions with an unknown structural cause. This data will be used to perform structure-guided antibody design to further enhance their effector functions for the benefit of human health.
Aim 3: Discovering Structural Determinants
The third aim is to discover the structural determinants orchestrating antibody-mediated phagocytosis by macrophages using SRcryoCLEM.
This immunologically pivotal mechanism is poorly understood but is being exploited as a next-generation therapeutic. Our data will provide crucial insights into the fundamental biological processes underlying macrophage function, allowing therapeutic gain.
Financiële details & Tijdlijn
Financiële details
| Subsidiebedrag | € 1.976.553 |
| Totale projectbegroting | € 1.976.553 |
Tijdlijn
| Startdatum | 1-5-2025 |
| Einddatum | 30-4-2030 |
| Subsidiejaar | 2025 |
Partners & Locaties
Projectpartners
- UNIVERSITY OF BRISTOLpenvoerder
Land(en)
Vergelijkbare projecten binnen European Research Council
| Project | Regeling | Bedrag | Jaar | Actie |
|---|---|---|---|---|
MANUNKIND: Determinants and Dynamics of Collaborative ExploitationThis project aims to develop a game theoretic framework to analyze the psychological and strategic dynamics of collaborative exploitation, informing policies to combat modern slavery. | ERC STG | € 1.497.749 | 2022 | Details |
Elucidating the phenotypic convergence of proliferation reduction under growth-induced pressureThe UnderPressure project aims to investigate how mechanical constraints from 3D crowding affect cell proliferation and signaling in various organisms, with potential applications in reducing cancer chemoresistance. | ERC STG | € 1.498.280 | 2022 | Details |
Uncovering the mechanisms of action of an antiviral bacteriumThis project aims to uncover the mechanisms behind Wolbachia's antiviral protection in insects and develop tools for studying symbiont gene function. | ERC STG | € 1.500.000 | 2023 | Details |
The Ethics of Loneliness and SociabilityThis project aims to develop a normative theory of loneliness by analyzing ethical responsibilities of individuals and societies to prevent and alleviate loneliness, establishing a new philosophical sub-field. | ERC STG | € 1.025.860 | 2023 | Details |
MANUNKIND: Determinants and Dynamics of Collaborative Exploitation
This project aims to develop a game theoretic framework to analyze the psychological and strategic dynamics of collaborative exploitation, informing policies to combat modern slavery.
Elucidating the phenotypic convergence of proliferation reduction under growth-induced pressure
The UnderPressure project aims to investigate how mechanical constraints from 3D crowding affect cell proliferation and signaling in various organisms, with potential applications in reducing cancer chemoresistance.
Uncovering the mechanisms of action of an antiviral bacterium
This project aims to uncover the mechanisms behind Wolbachia's antiviral protection in insects and develop tools for studying symbiont gene function.
The Ethics of Loneliness and Sociability
This project aims to develop a normative theory of loneliness by analyzing ethical responsibilities of individuals and societies to prevent and alleviate loneliness, establishing a new philosophical sub-field.
Vergelijkbare projecten uit andere regelingen
| Project | Regeling | Bedrag | Jaar | Actie |
|---|---|---|---|---|
Phase Contrast STEM for Cryo-EMThis project aims to enhance cryo-electron tomography in biology using high-resolution scanning transmission EM, improving imaging quality and enabling new insights into cellular structures. | ERC ADG | € 2.499.987 | 2022 | Details |
Stress-induced structural and organizational adaptations of the cellular translation machineryThis project aims to investigate how cellular strategies for maintaining protein homeostasis affect ribosome structure and organization under stress, using cryo-electron tomography for detailed insights relevant to neurodegenerative diseases. | ERC STG | € 1.498.832 | 2023 | Details |
Streamlining structural biology: Developing a high-throughput cloud-based cryo-electron tomography platformDevelop a cloud-based workflow for automated high-throughput cryo-electron tomography data analysis to democratize access and reduce processing time, enhancing molecular research. | ERC POC | € 150.000 | 2023 | Details |
Making time-resolved cryo-EM available for the community of structural biologists: validate, improve, deriskThis project aims to develop and commercialize a novel time-resolved cryo-EM sample preparation method to enhance protein structure analysis and accessibility for users. | ERC POC | € 150.000 | 2024 | Details |
Phase Contrast STEM for Cryo-EM
This project aims to enhance cryo-electron tomography in biology using high-resolution scanning transmission EM, improving imaging quality and enabling new insights into cellular structures.
Stress-induced structural and organizational adaptations of the cellular translation machinery
This project aims to investigate how cellular strategies for maintaining protein homeostasis affect ribosome structure and organization under stress, using cryo-electron tomography for detailed insights relevant to neurodegenerative diseases.
Streamlining structural biology: Developing a high-throughput cloud-based cryo-electron tomography platform
Develop a cloud-based workflow for automated high-throughput cryo-electron tomography data analysis to democratize access and reduce processing time, enhancing molecular research.
Making time-resolved cryo-EM available for the community of structural biologists: validate, improve, derisk
This project aims to develop and commercialize a novel time-resolved cryo-EM sample preparation method to enhance protein structure analysis and accessibility for users.