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Integrative System Biology of iPSC-induced Neurons for Identifying Novel Drug Targets

State/Province Full: 
United States

Autism is quickly emerging as one of the most prevalent developmental diseases of our time. Despite the large amount of scientific discoveries regarding the etiology, pathology, and clinical assessments of this complex, heterogeneous disorder, diagnostic and therapeutic biomarkers that could enable early diagnosis and therapy are lacking. Identification of clinically relevant biomarkers in brain tissue is clearly rendered more difficult by the unavailability of the tissue, the complexity and heterogeneity of the brain, and the fact that peripheral tissues such as blood, urine and even cerebrospinal fluid might not reflect brain pathology. This research laboratory is experiences in the systems biology approach to neurodevelopmental diseases and autism. Systems biology sciences look at the organism as a whole, rather than focusing on a single gene or molecule of interest. We focus on metabolomics, the study of all small molecules or metabolites which are present in a given tissue. These metabolites include amino acids, fatty acids, sugars and other molecules required for the proper functioning of the cells and tissues. Recent investigations of the metabolic status of autistic patients have indicated that certain metabolic impairments may underlie autism, specifically problems in fatty acid and energy metabolism in the nerve cells. To identify small molecules in different regions of the brain, we use magnetic resonance spectroscopy. The researchers have completed a study on 25 autistic children who underwent brain scan of several regions implicated in autism. This study aims to extend the team’s imaging and spectroscopy research to specific patients in whom some abnormalities in the metabolomic content of the brain have been identified. To further explore the basic mechanisms of these metabolic abnormalities, the fellow and mentors aim to develop a cellular model of autism which uses patient-specific induced pluripotent stem cells (iPS) and prompts them to differentiate into neurons. In those patient-specific neurons, they will study the metabolome abnormalities as well as their gene regulation. They expect to discover not only new molecular mechanisms that might be important for the development of autism, but also new therapeutic targets which might help alleviate the disease.