Inflammation: Exploring the Importance of Rac-GEF Activity

Lead Research Organisation: University of Cambridge
Department Name: Plant Sciences

Abstract

P-Rex and Vav are two related protein families important for the recruitment of white blood cells to sites of infection during the inflammatory response. They are GEF proteins that activate the small GTPase Rac, and this catalytic Rac-GEF activity is crucial for most of their functions. In leukocytes, individual GEF proteins from both families, P-Rex1 and Vav1, cooperate in the activation of Rac and of Rac-dependent cell responses. However, Vav1 can also signal independently of its Rac-GEF activity, and preliminary evidence suggests that P-Rex1 also has GEF-activity independent roles. The objective of this studentship is to assess the importance of the P-Rex1 and Vav1 Rac-GEF activities for leukocyte recruitment during inflammation and for the ability of leukocytes to clear infections.
The PhD student will determine the effects of P-Rex1 and Vav1 expression and their Rac-GEF activities on leukocyte recruitment during inflammation and infection. S/he will learn to analyse Rac-GEF signalling pathway activity, generate genetically-modified mouse strains, assess leukocyte host defence responses in isolated cells and in vivo, and become an expert in small GTPase and related pathways and in the mechanisms regulating inflammation and host defence.

Publications

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Pantarelli C (2018) Rac-GTPases and Rac-GEFs in neutrophil adhesion, migration and recruitment. in European journal of clinical investigation

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011194/1 01/10/2015 30/09/2023
1646515 Studentship BB/M011194/1 01/10/2015 30/09/2019 Chiara Pantarelli
 
Description As part of my PhD, I am evaluating the importance of two signalling proteins for the recruitment of white blood cells to sites of infection, Norbin and P-Rex respectively. During this research project, I am becoming an expert of the biochemical pathway correlating to the immune system. I have learned a broad range of techniques to assess the function of neutrophils ( the most abundant white blood cells in our body) in vitro and in vivo characterising the phenotype of my mouse strains. Our current work aims to identify the functional roles of Norbin and of the P-Rex1/Norbin interaction in neutrophils. We generated new genetically-modified mouse strains and assess signalling and responses of isolated neutrophils from these mice, as well as the tissue recruitment and immune functions of neutrophils in vivo. Neutrophils from these new mouse strains show surprising phenotypes in there ability to clear the inflammation. The genetically modified mice show altered neutrophil recruitment and antibacterial immunity. We are planning to obtain human samples that have developed a chronic inflammation disease. Our aim will be to assess any alteration of the Norbin protein in these samples.
Exploitation Route My findings could reveal the importance role of Norbin, as a new protein, in which its normal presence has a considerable impact during the inflammation, playing an autoimmune role.
Sectors Pharmaceuticals and Medical Biotechnology

URL https://www.ncbi.nlm.nih.gov/pubmed/26792863
 
Description Afternoon tea with a local adult community group 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Particularly, I enjoyed one of my latest experience with a local adult community group, which is very different from the usual school and family audiences I have worked with. I decided to get involved in this new activity because I thought it would be a great opportunity for me to practice my communication skills with people I hadn't met before. I wanted to challenge myself and share my PhD experiences with people who may not know what is required in planning and performing an experiment, or how research is funded. The challenge was to break the ice and try to explain, in non-scientific language, what my research project is about and what my research might help us to understand in the future.
Year(s) Of Engagement Activity 2017
 
Description Science Outreach events Coordinator 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact I am currently doing a Professional Internship in MedImmune/AstraZeneca (AZ), supporting their outreach and public engagement work, primarily in delivering their contribution to the Cambridge Science Festival in March 2018. There are many schools visits lined up for the next months where we will try how the science activity works before bringing to the Festival. In MedImmune I am contributing to design the science activity and promote the Cambridge Science Festival internally, coordinating the handcraft materials and the volunteers who will help us during the event up to three days in March during the festival. I am taking part in lots of meeting, interfacing myself with experts in communication and outreach events. Despite being a newcomer, it's wonderful to collaborate with professional and being able to express my opinion that often is taking into considerations to improve the project.
Year(s) Of Engagement Activity 2018
URL https://www.sciencefestival.cam.ac.uk/