PROJECT 1: The Inflammatory Bowel Diseases (IBD), Crohn's disease and ulcerative colitis are genetically complex diseases in which the environment is also a significant contributor. More than 200 genetic variants have been associated with the development of IBD and there have also been considerable insights of microbiome associations with IBD. To date, most genetic studies have used platforms that are designed to capture common genetic signals. We have shown that whole exome sequencing (WES) can identify rare variants that add further to the understanding of the genetic structure of IBD. Our preliminary data also suggests that the creation of polygenic gene risk scores (GRS) can add a powerful dimension to discovering additional genetic signals and also to elucidating the complex relationship with the microbiome. In this proposal we will be utilizing next generation sequencing approaches, single cell technology, together with novel genetic and systems biology approaches to further understand the underlying causes of IBD. We will generate additional WES data in IBD subjects selected as a consequence of their extreme phenotypes or GRS and enriching populations either genetically or by extreme phenotype will likely enhance variant discovery further. We will identify protective variants in healthy controls genetically `primed' to develop CD and also in UC subjects genetically predisposed to severe disease. Genetic variation in genes of the NFkB pathway are enriched in severe UC and we will extract monocytes from UC subjects with high and low NFkB GRSs and perform RNAseq and single cell sequencing on these subjects to better understand the functional consequences of these genetic variants. We will expand upon our striking observation that GRS has a profound effect on the mucosal metabolome in both controls and IBD cases and we will extend these investigations to try and better understand the ability of the serum metabolome to reflect the mucosal signature. Our preliminary data strongly support the hypothesis that disease and pathway specific GRS will identify molecular extremes/clusters of IBD subjects: facilitating novel variant discovery; elucidating functional effects consequent of IBD-associated variants; and delineating genetic effects on host-microbiomal relationships.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK046763-25
Application #
9342775
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
25
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Weiser, Matthew; Simon, Jeremy M; Kochar, Bharati et al. (2018) Molecular classification of Crohn's disease reveals two clinically relevant subtypes. Gut 67:36-42
Seo, Goo-Young; Shui, Jr-Wen; Takahashi, Daisuke et al. (2018) LIGHT-HVEM Signaling in Innate Lymphoid Cell Subsets Protects Against Enteric Bacterial Infection. Cell Host Microbe 24:249-260.e4
Clerc, Florent; Novokmet, Mislav; Dotz, Viktoria et al. (2018) Plasma N-Glycan Signatures Are Associated With Features of Inflammatory Bowel Diseases. Gastroenterology 155:829-843
Rivas, Manuel A; Avila, Brandon E; Koskela, Jukka et al. (2018) Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population. PLoS Genet 14:e1007329
Hong, Myunghee; Ye, Byong Duk; Yang, Suk-Kyun et al. (2018) Immunochip Meta-Analysis of Inflammatory Bowel Disease Identifies Three Novel Loci and Four Novel Associations in Previously Reported Loci. J Crohns Colitis 12:730-741
Freise, Amanda C; Zettlitz, Kirstin A; Salazar, Felix B et al. (2018) Immuno-PET in Inflammatory Bowel Disease: Imaging CD4-Positive T Cells in a Murine Model of Colitis. J Nucl Med 59:980-985
Šimurina, Mirna; de Haan, Noortje; Vu?kovi?, Frano et al. (2018) Glycosylation of Immunoglobulin G Associates With Clinical Features of Inflammatory Bowel Diseases. Gastroenterology 154:1320-1333.e10
Leonardi, Irina; Li, Xin; Semon, Alexa et al. (2018) CX3CR1+ mononuclear phagocytes control immunity to intestinal fungi. Science 359:232-236
Hui, Ken Y; Fernandez-Hernandez, Heriberto; Hu, Jianzhong et al. (2018) Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Sci Transl Med 10:
Schwerd, T; Bryant, R V; Pandey, S et al. (2018) NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease. Mucosal Immunol 11:562-574

Showing the most recent 10 out of 277 publications