Postdoc: Discovering Car T Cell Biophysics with
1 week geleden
**Postdoc: Discovering CAR T cell biophysics with single-molecule TIRF microscopy**:
**Work Activities**:
Notably, a complex spatio-temporal dynamics is thought to be central to CAR T cell activation, but is difficult to measure and hence remains poorly understood. That the activation relies on the movement and association of many receptors and accesory proteins in an orchestrated manner is a fascinating notion. By addressing this question at the molecular level, you will have the opportunity to elucidate the underlying dynamic mechanisms for the first time. More generally, the model system for cell-cell contact dynamics that you will use and advance pushes the boundaries of biophysical measurement techniques, and can be applied to many other systems.
Equipping T cells from patients with chimeric antigen receptors (CARs) has promised a new era of cancer therapies. CARs are synthetic transmembrane receptors that are designed to recognise a tumour antigen and activate T cell signalling pathways, directing T cells against the tumour. However, despite the quick success of specific CAR designs, it has become clear that it is extremely difficult to predict how changes to CAR designs affect their signalling and therefore efficiency. This lack of predictability is, at least in part, due to our very limited understanding of the molecular mechanisms of CAR signalling. The aim of this project is to reveal the dynamics of CAR function and signalling for the first time at the single-molecule level. You will use advanced single-molecule and single-cell imaging combined with novel synthetic biology approaches to directly measure the striking hypothesized CAR organisation into signalling clusters in membranes and downstream signalling dynamics to, among other questions, elucidate the role of the co-stimulatory domain of these receptors and parallel activation of co-stimulatory receptors. You will combine these experiments with investigating CAR T cell avidities using Lumicks z-Movi method in collaboration with Lumicks.
This project has now become possible owing to recent technical advances, including new in vitro assays and imaging approaches developed by our lab and others (JACS 2013, Nat Immun 2016, PNAS 2019, Nat Commun 2021, 2023). You will develop new microscopy-based assays to enable this first dynamic view on how CARs re-wire T-cell signalling cascades and to identify design principles for tuning CAR activation.
**Qualifications**:
You need to meet the requirements for a doctors-degree (PhD) and must have research experience in a non-Dutch academic environment. We are looking for an biophysicist who has worked with single-molecule fluorescence techniques, or alternatively a (bio)chemist or molecular immunologist with a strong and demonstratable interest in single-molecule approaches. Experience with quantitative fluorescence microscopy and programming skills to handle automated analysis of image data is highly desired; knowledge of protein biochemistry and/or model lipid systems would be an advantage. You should like the idea of working in a collaborative, ambitious and international environment. Excellent verbal and written English skills are essential.
**Work environment**:
**Ganzinger group -** We are a supportive and social research group of about 8 PhD students and postdocs, which work together in small teams on various projects from immunological signalling to signalling in synthetic cells. The collaborative and social atmosphere includes to the other research groups at the AMOLF institute at the Science Park in Amsterdam. Our group has been making recent technical advances, including a new single-molecule tracking method based on DNA-PAINT that we recently developed (Nat Commun 2021, Nat Commun 2023), new in vitro assays (ACS Syn Biol 2021, ACS Omega 2024), and imaging approaches developed by our lab and others (JACS 2013, Nat Immun 2016, PNAS 2019), all to closely investigate the intricate molecular details of cellular signaling.
**Tans group**: We form a lively and close-knit research group of about 10 PhD students and postdocs, which work together in small teams on various projects in a highly supportive and social atmosphere. The Tans group studies the dynamics of single proteins (Nature 2013, Nature 2016, Nature 2020) and single cells (Nature 2014, Curr. Biol. 2018, Nature 2020) using novel experimental approaches.
**Working conditions**:
- The working atmosphere at the institute is largely determined by young, enthusiastic, mostly foreign employees. Communication is informal and runs through short lines of communication.
- The position is intended as full-time (40 hours / week, 12 months / year) appointment in the service of the Netherlands Foundation of Scientific Research Institutes (NWO-I) for a maximum duration of 2 years.
- Salary is in scale 10 (CAO-OI) which starts at 4.065 Euro’s gross per month, and a range of employment benefits.
**More information?**:
**Application**:
- Online scre
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