Dissecting molecular pathways associated with autism using stem cell-based models and genomics approaches

The study of complex human diseases, such as autism, is hampered by lack of access to patient-derived tissues. Human neuronal tissues, only available from cadavers, are very limited in supply and typically of poor viability. To circumvent these limitations, disease research resorts to using immortalized human cell lines and animal tissues. However, modeling diseases with these materials often does not capture the salient molecular and cell physiologic aspects of the diseases. Disease modeling has recently made a tremendous leap forward with the ability to make patient specific iPSC (induced pluripotent stem cells). By directed in vitro differentiation, the human iPSC can be converted to human cell types of interest, including neurons. My team is generating neural progenitors and functional human neurons by directed differentiation of pluripotent stem cells derived from affected patients. These patient-derived neurons and their precursors provide an excellent experimental platform to investigate the molecular and biological pathways that are perturbed in the initiation and/or progression of the disease. In addition, we are creating isogenic iPSC lines that are CRISPR-edited to express single genetic variants identified in QBRI’s Autism genetics program. My group will compare wild-type vs. patient-specific (or isogenic lines) neuronal cells using functional assays and genomics approaches to reveal the molecular mechanisms underlying the disease pathology. Considering the goals and strengths of ongoing research within the Neurological Disorders Research Center at QBRI, I plan to focus my disease modeling research primarily on autism spectrum disorders (ASD). The molecular pathways identified in this research that are linked to ASD will: 1) provide candidate markers for clinical diagnosis and tracking of the disease progression; 2) identify therapeutic targets for drug discovery efforts; and 3) establish robust assays for drug screening.

Hamad Bin Khalifa University (HBKU)