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Supervisors names
Tessa C
Ching In Lau
Background
This project will test the hypothesis that dysregulated Hedgehog signalling to T-cells contributes to obesity, obesity-induced inflammation and metabolic disease in children, in the general population and in the rare autosomal recessive disorder, Bardet-Biedl syndrome (BBS). Children with BBS show early onset obesity and high prevalence of type 2 diabetes and autoimmune disease [1]. In BBS canonical Hedgehog signalling is disrupted by defects in genes required for function of the primary cilium [2]. We have shown that physiological Hedgehog signalling to T-cells is broadly anti-inflammatory and induces T regulatory cell (Treg) differentiation and function [3,4]. The importance of Treg in protecting against obesity and metabolic disease is well established [5].
Aims
We aim to investigate the role of Hedgehog signalling to T-cells in homeostasis of adipose tissue, and prevention of obesity, obesity-induced inflammation and metabolic disease, with goal of identifying new strategies to treat metabolic disorders in children with BBS.
Objectives
1. Test the hypothesis that physiological levels of Hedgehog pathway activation in T-cells protect against obesity, inflammation and metabolic disease by inducing immune regulation and homeostasis of adipose tissue.
2. Dissect contribution of different effector and regulatory T-cell populations to Hedgehog’s influence on obesity and metabolic disease.
3. Test hypothesis that dysregulated Hedeghog signalling to immune cells contributes to early onset obesity and metabolic disease in BBS.
4. Test impact of pharmaceutical, cellular and genetic modifications of Hedgehog pathway on obesity in BBS models and fat-diet-induced-obesity models.
Methods and experimental strategy
We will carry out in vitro experiments with T-cells from BBS patients and healthy controls and in vivo experiments in mouse models of BBS and of obesity induced by high fat/high-sugar diet in WT and conditional Hedgehog- pathway-mutants. We will test if pharmacological, cellular or genetic modifications can improve obesity and insulin sensitivity in the mouse models.
The project will provide training in flow cytometry, microscopy, molecular biology, tissue culture and in vitro functional assays, RNAsequencing and analysis of its datasets, genetic mouse models (see references 1-5).
Timeline: Year 1: establishment of obese BBS mouse models (breeding and diet), analysis of Hh signalling in BBS T-cells and thymus; Year 2: analysis of patient samples, RNAseq from patient samples and mouse models; Year 3: pharmacological treatments and adoptive transfer into BBS models; write manuscripts and thesis.
References
1. Tsyklauri O, Niederlova V, Forsythe E, Prasai A, Drobek A, Kasparek P, et al. Bardet-Biedl Syndrome ciliopathy is linked to altered hematopoiesis and dysregulated self-tolerance. EMBO Rep 2021; 22:e50785.
2. Hey CAB, Larsen LJ, Tumer Z, Brondum-Nielsen K, Gronskov K, Hjortshoj TD, et al. BBS Proteins Affect Ciliogenesis and Are Essential for Hedgehog Signaling, but Not for Formation of iPSC- Derived RPE-65 Expressing RPE-Like Cells. Int J Mol Sci 2021; 22.
3. Papaioannou E, Yanez DC, Ross S, Lau CI, Solanki A, Chawda MM, et al. Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation. J Clin Invest 2019; 129:3153-70.
4. Lau CI, Yanez DC, Papaioannou E, Ross S, Crompton T. Sonic Hedgehog signalling in the regulation of barrier tissue homeostasis and inflammation. FEBS J 2022.
https://doi.org/10.1111/febs.16222
5. Wara AK, Wang S, Wu C, Fang F, Haemmig S, Weber BN, et al. KLF10 Deficiency in CD4(+) T Cells Triggers Obesity, Insulin Resistance, and Fatty Liver. Cell Rep 2020; 33:108550.
Contact
Tessa Crompton and Ching In Lau (t.crompton@ucl.ac.uk and chingin.lau@ucl.ac.uk)