LABORATORY BASED RESEARCH | Smithrahman Group

For more details on optineurin and its role in autophagy, immunity and human disease please follow the link below to a Research Topics in Frontier in Immunology

The Role of Optineurin in Immunity and Immune-Mediated Diseases

Autophagy Research

Genetic studies have identified abnormalities in the autophagy process in individuals with inflammatory bowel disease, neurodegeneration and cancer. Autophagy is a natural process in which the body's cells remove damaged components or infective agents such as bacteria and viruses.

Our group is interested in understanding how ATG16L1 and Optineurin (OPTN), two proteins associated with autophagy and inflammatory bowel disease, function in mucosal immunity and cellular regulation.

Our previous autophagy related publications

OPTN recruitment to a Golgi-proximal compartment regulates immune signalling and cytokine secretion. O'Loughlin et al J Cell Sci. 2020 Jun 15;133(12):jcs239822. doi: 10.1242/jcs.239822.
Selective Autophagy of Mitochondria on a Ubiquitin-Endoplasmic-Reticulum Platform. Gudmundsson et al . Dev Cell. 2019 Sep 9;50(5):627-643.e5. doi: 10.1016/j.devcel.2019.06.016.
Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis. Tschurtschenthaler et al. J Exp Med. 2017 Feb;214(2):401-422. doi: 10.1084/jem.20160791.
Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis. Chew et al. Dis Model Mech. 2015 Aug 1;8(8):817-29. doi: 10.1242/dmm.020362.
Disruption of macrophage pro-inflammatory cytokine release in Crohn's disease is associated with reduced optineurin expression in a subset of patients. Smith et al. Immunology. 2015 Jan;144(1):45-55. doi: 10.1111/imm.12338.

Microbiome

The microbiome is the collection of all microbes, such as bacteria, fungi and viruses, that naturally live on our bodies and inside us. The human microbiome consists of the 10-100 trillion microbial cells that are primarily found in the gut. Changes in the composition of the microbiome have been linked with numerous human conditions and current research is focused on understanding how these alterations influence disease progression and response to therapies.

We are currently studying the oral-gut axis and investigating the link between inflammatory bowel disease and oral inflammation. This work is funded by Biomedical Research Centre UCL/UCLH Oral & Dental Medicine theme.

Our previous microbiome related publications

The Role of Diet and Gut Microbiota in Regulating Gastrointestinal and Inflammatory Disease. Gill PA, et al. Front Immunol. 2022 Apr 5;13:866059. doi: 10.3389/fimmu.2022.866059. eCollection 2022.
Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease. Matei et al. Med (N Y). 2021 Jul 9;2(7):864-883.e9. doi: 10.1016/j.medj.2021.04.013.
The role of the microbiome in gastrointestinal inflammation. Sanders et al. Biosci Rep. 2021 Jun 25;41(6):BSR20203850. doi: 10.1042/BSR20203850.
Antimicrobial surfaces: A need for stewardship? Cassidy et al. PLoS Pathog. 2020 Oct 15;16(10):e1008880. doi: 10.1371/journal.ppat.1008880. eCollection 2020 Oct.
The Microbiome and Radiation Induced-Bowel Injury: Evidence for Potential Mechanistic Role in Disease Pathogenesis. Kumagai et al. Nutrients. 2018 Oct 2;10(10):1405. doi: 10.3390/nu10101405.
The oral microbiome. Shaw et al. Emerg Top Life Sci. 2017 Nov 30;1(4):287-296. doi: 10.1042/ETLS20170040.
The Human Salivary Microbiome Is Shaped by Shared Environment Rather than Genetics: Evidence from a Large Family of Closely Related Individuals. Shaw L,et al. mBio. 2017 Sep 12;8(5):e01237-17. doi: 10.1128/mBio.01237-17.

Gut Organoids

Gut organoids or mini-guts are generated from pinch biopsy samples taken from volunteers undergoing routine endoscopy. The organoids provide a lab based method to study the complex cellular responses that occur within the gut.

We are currently working on the epithelial cell regulation of inflammation in individuals with inflammatory bowel disease. The project is funded by Crohn's and Colitis UK.

Innate Immunity

The innate immune system acts as the first line of defence against invading pathogens. The innate immune response is activated immediately upon insult, but does not result in longterm memory. Innate immunity to pathogens relies on pattern recognition receptors (PRRs), which allow cells to detect and respond rapidly to a wide range of pathogens that share common structures, known as pathogen associated molecular patterns (PAMPs). Activation of PRRs results in the release of inflammatory mediators which orchestrate the ensuing immune response. Abnormalities in innate immunity are associated with the development of a range of disease and our research demonstrated that Crohn's disease patients have an attenuated innate immune response, which predisposes these individuals to chronic bowel inflammation.

Our current research is focused on understanding how defects in innate immunity result in the development of human disease.

Our previous Innate Immunity related publications

Spatiotemporal proteomic profiling of the pro-inflammatory response to lipopolysaccharide in the THP-1 human leukaemia cell line. Mulvey et al. Nat Commun. 2021 Oct 1;12(1):5773. doi: 10.1038/s41467-021-26000-9
OPTN recruitment to a Golgi-proximal compartment regulates immune signalling and cytokine secretion. O'Loughlin et al J Cell Sci. 2020 Jun 15;133(12):jcs239822. doi: 10.1242/jcs.239822.
Elevation in Cell Cycle and Protein Metabolism Gene Transcription in Inactive Colonic Tissue From Icelandic Patients With Ulcerative Colitis. Vinayaga-Pavan et al. Inflamm Bowel Dis. 2019 Jan 10;25(2):317-327. doi: 10.1093/ibd/izy350.
Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation. O'Shea NR, et al. J Crohns Colitis. 2016 Dec;10(12):1417-1427. doi: 10.1093/ecco-jcc/jjw111. Epub 2016 May 25.
Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis. Chew et al. Dis Model Mech. 2015 Aug 1;8(8):817-29. doi: 10.1242/dmm.020362.
Disruption of macrophage pro-inflammatory cytokine release in Crohn's disease is associated with reduced optineurin expression in a subset of patients. Smith AM, et al. Immunology. 2015 Jan;144(1):45-55. doi: 10.1111/imm.12338.
The role of the innate immune system in granulomatous disorders. Petersen &, Smith. Front Immunol. 2013 May 24;4:120. doi: 10.3389/fimmu.2013.00120. eCollection 2013.
Defective tumor necrosis factor release from Crohn's disease macrophages in response to Toll-like receptor activation: relationship to phenotype and genome-wide association susceptibility loci. Sewell et al. Inflamm Bowel Dis. 2012 Nov;18(11):2120-7. doi: 10.1002/ibd.22952. Epub 2012 Mar 20.
Crohn's disease as an immunodeficiency. Hayee et al. Expert Rev Clin Immunol. 2010 Jul;6(4):585-96. doi: 10.1586/eci.10.32.
Impaired macrophage function following bacterial stimulation in chronic granulomatous disease. Rahman et al. Immunology. 2009 Oct;128(2):253-9. doi: 10.1111/j.1365-2567.2009.03112.x.
Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. Smith et al. J Exp Med. 2009 Aug 31;206(9):1883-97. doi: 10.1084/jem.20091233. Epub 2009 Aug 3.

Digestive Diseases Research Group
University College London
Principle Investigators Professor Andrew Smith and Dr Farooq Rahman

LABORATORY BASED RESEARCH PROJECTS