Akademik Veri Yönetim Sistemi
Diğer Ülkelerdeki Kamu Kurumları Tarafından Desteklenmiş Proje, 2022 - 2025
Inflammatory bowel disease (IBD) is characterized by chronic, debilitating inflammation of the gut and typically presents as Crohn’s disease or ulcerative colitis. However, very early-onset IBD (VEOIBD), defined as IBD before the age of 6, is distinct. VEOIBD is more severe, can be fatal without proper treatment, and often does not respond to conventional therapy, including surgery. Genetics contributes a significant factor to the etiology of VEOIBD, and in many cases, the cause is monogenic. Therefore, there is a higher frequency of VEOIBD in populations with high consanguinity, such as in Qatar and other countries in the Middle East. Defects in various genes have been found to cause VEOIBD, however, they only account for disease in about 30% of cases. The majority of affected children do not have defects in those genes and remain undiagnosed, indicating the potential for new VEOIBD genes to be discovered. Evidence suggests that earlier diagnosis and treatment increases the chances of survival and reduces the detrimental effects on the child’s development. The type of treatment is dependent on the specific genetic defect. Thus, an accurate molecular diagnosis is instrumental for guiding therapy decisions. For instance, hematopoietic stem cell transplantation (HSCT) can often be curative for patients with gene defects predominantly impacting immune cells, however HSCT is ineffective for patients with mutations causing an epithelial barrier defect. Importantly, studying the function of the affected genes and their contribution to disease etiology can inform the use of targeted therapies and the implementation of personalized medicine. The main goal of this research proposal is to identify the causes of VEOIBD afflicting children in the region and provide definitive molecular diagnoses. To achieve this goal, our specific aims are: (1) Establish our very early onset IBD cohort, including recruitment, collection of detailed clinical data, and specimen collection/storage. (2) Identify potentially deleterious, disease-causative variants in the patients. We will whole genome sequence the parents and the affected family members to identify the mutations associated with disease. (3) Determine the functional consequence of the variants identified and how they may influence disease. Candidate disease mutations identified from the sequencing analysis will be functionally characterized in patient primary cells and/or modelled in cell lines or patient biopsy-derived organoids. The study of these single gene defects and how they impact gut homeostasis will also help elucidate the role of these individual genes in the development of the more common polygenic forms of IBD. Overall, the proposed study is significant because it will (a) identify new VEOIBD-associated genes, (b) further our understanding of IBD etiology, and (c) facilitate the implementation of precision medicine in VEOIBD patients.