This application is designed to provide Jean-Paul Achkar, MD with a program of mentored, patient-oriented research. The proposed plan of education and training would allow the PI to build on a foundation of research that he has pursued to date and to further develop his research career with the ultimate goal of becoming an independent funded clinical investigator in inflammatory bowel disease genetics. This training would include class work at Case Western Reserve University with the goal of obtaining a Masters degree. This proposal outlines an approach to address our central hypotheses that: 1. defining more homogeneous subgroups of Crohn's disease (CD) will help in finding CD-susceptibility genes and in understanding underlying pathogenesis of CD, 2. phenotypic information can be used to identify more homogeneous subgroups of CD and 3. similar to findings with NOD2/CARD15 variants, abnormalities in innate host defense involving Paneth cells account for susceptibility to CD in different patient subgroups. We propose to address these hypotheses by conducting initiatives aimed at identifying more homogeneous CD subgroups by: 1. using an unbiased genetic approach of analyzing stratified genome-wide linkage, and 2. performing directed candidate gene studies of Paneth cell products.
Our specific aims are:
Aim #1 : Collect detailed phenotypic information on CD-affected individuals for whom we already have genotypic data from genome scans and then perform stratified genome-wide linkage analyses. Stratification will be based on defining subsets of CD-affected individuals by specific phenotypic parameters. Through collaborative efforts, the PI has access to a large IBD genome scan dataset. The PI will perform detailed phenotyping of CD-affected relative pairs who were part of this genome scan dataset. We will then perform genome-wide linkage analyses of data subsets defined by specific phenotypic parameters.
Aim #2 : Perform a candidate gene, case-control, haplotype-based association study to identify mutations in Paneth cell products that may predispose to the development of CD in subgroups of patients. The PI will continue to recruit patients and controls for an IBD DMA bank that he recently started. This collection will then be used to pursue a case-control, haplotype-based analysis of Paneth cell candidate genes.
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