Investigation of the Discovery, Molecular Characterization, and Roles of Genes Associated with Sleep Disorders in Disease Pathogenesis - (:unkn) unknown (My University, 2024)
Sleep disorders are classified into six categories: insomnia, sleep-related breathing disorders, central disorders of hypersomnolence, circadian rhythm sleep-wake disorders, parasomnias, and sleep-related movement disorders. Although the molecular mechanism of sleep is not fully understood, it is known that the circadian rhythm\"s most prominent function is regulating sleep-wake cycles. In this project, priority will be given to sampling and detailed phenotyping of patients with circadian rhythm sleep-wake disorders and insomnia, as well as their family members. Our research team consists of experts in sleep neurology, human genetics, bioinformatics, molecular biology, and molecular biochemistry, who are recognized nationally and internationally for their high impact publications in these fields. Our project partner, Ueda and their team, have provided us with sleep monitoring devices (actigraphs) for clinical phenotyping of our familial cohort. This will enable detailed phenotyping of family members, resulting in the creation of a cohort comprising well-phenotyped and sub-grouped families spanning 3-4 generations, including numerous affected and unaffected individuals, for the first time worldwide. Our team is experienced in this regard. In our previous pilot studies on the project topic, we showed an association between a mutation in the CRY1 gene and delayed sleep phase disorder (DSPD) using a reverse phenotyping approach in families. We introduced a new conceptual approach termed \"reverse phenotyping,\" which could be utilized for studying the human genome, in a leading article in Nature Genetics. Through reverse phenotyping, we demonstrated that individuals carrying the CRY1 mutation exhibit symptoms and disorders indicative of ADHD in addition to DSPD. We aim to replicate these findings in a sleep cohort established within this project, which will comprise well-phenotyped and sub-grouped families spanning 3-4 generations, including numerous affected and unaffected individuals, for the first time worldwide. Whole exome sequencing will be performed on DNA samples isolated from 1-2 individuals from each family in our cohort. Genomic analyses will be conducted using our developed algorithm. Identified variants will be interpreted and prioritized using Phenome-Wide Association Studies (PheWAS) in the BioMe clinical database. If necessary, homozygosity and linkage mapping studies will be conducted. Sanger sequencing will be performed to genetically confirm candidate genes associated with the disease, and causative mutations inherited within the family will be identified. Functional in vitro studies will be conducted for candidate genes with strengthened genetic evidence. Additionally, our project partner, Ueda and their team, are experienced in creating and testing mouse knock-out and knock-in models associated with sleep phenotypes. Candidates validated in vitro can be rapidly phenotyped in mice. The uniqueness of our study lies in the use of extensively phenotyped families, sampling and phenotyping of large families to facilitate the identification of genetic variants associated with the disease phenotype, the utilization of current genomic methods, innovative and population-appropriate rare variant analysis and prioritization methods developed by us, the testing of our algorithm primarily on known circadian rhythm and sleep genes, and finally, gaining mechanistic insights into molecular mechanisms through in vitro experiments. In an era where genomic projects are focused on diseases, the identification of causative mutations inherited in sleep state and behavioral disorders, along with the knowledge gained about the pathogenesis of the disease, is expected to significantly contribute to international scientific competitiveness and to highlight \"Big Data\" initiatives in our country
Keywords: Yaşam Bilimleri; Biyoinformatik; Diğer; Moleküler Biyoloji ve Genetik; Genomiks; Temel Bilimler; Life Sciences; Bioinformatics; Other; Molecular Biology and Genetics; Genomics; Natural Sciences; Temel Bilimler (Sci); Yaşam Bilimleri (Life); Doğa Bilimleri Genel; Biyoloji Ve Biyokimya; Moleküler Biyoloji Ve Genetik; Çok Disiplinli Bilimler; Matematiksel Ve Hesaplamalı Biyoloji; Hücre Biyolojisi; Natural Sciences (Sci); Life Sciences (Life); Natural Sciences General; Biology & Biochemistry; Molecular Biology & Genetics; Multidisciplinary Sciences; Mathematical & Computational Biology; Cell Biology; Moleküler Biyoloji; Multidisipliner; Molecular Biology; Multidisciplinary