Wednesday, April 2, 2025
4/2/2025
The role of SMAD3 in gene networks underlying human brain activity - Although brain oscillations are a promising target for neuromodulation for cognitive disease, we have a poor understanding of the molecular mechanisms that lead to oscillatory activity. Motivated by this gap in knowledge, the Lega-Konopka collaboration has developed groundbreaking techniques to study the links between gene expression and memory-enhanced brain oscillations. By integrating gene expression data and memory-relevant iEEG signatures of the same human epilepsy patients, the collaboration discovered significant associations between memory-associated oscillations and specific gene expression patterns in the temporal pole. This work identified SMAD3 as a highly promising candidate for future study. We found strong links between SMAD3 gene expression and slow theta oscillations, which are uniquely important for human cognitive processes. We also found evidence that SMAD3 binds the regulatory elements of dozens of other genes connected with slow theta oscillations. Many of these putative SMAD3 gene targets are implicated in neuropsychiatric disorders characterized by cognitive dysfunction. Taken together, this evidence suggests that SMAD3 may coordinate the transcription of many genes that affect brain activity during memory processing. However, the brain-specific transcriptional targets of SMAD3 and the precise impact of SMAD3-mediated gene networks on human neural activity have yet to be definitively identified. The few studies on the functional role of SMAD3 in the brain showed that Smad3 knockout mice have impaired neurogenesis and long-term potentiation. Although animal models generate valuable insight into brain function, the complicated nature of human cognitive processes and related oscillations decreases the translational value of approaches using animals. To overcome these problems, I will use human organotypic slice culture (OSC) to define the function of SMAD3 in the regulation of memory-related gene networks and neural activity in the human brain. In Aim 1, I will enhance SMAD3 activity in human OSC then use snRNA-seq and snATAC-seq to identify SMAD3 gene targets. In Aim 2, I will demonstrate the ability to silence SMAD3 expression in human OSC using lentiviral shRNA constructs. I will then use high-density microelectrode array recordings to understand how the loss of SMAD3 impacts activity at the single neuron and network levels. By increasing our understanding of the mechanisms underlying memory-relevant brain activity, the completion of this project will lead us toward new therapies for cognitive disorders. This would be impossible without the stellar support of Drs. Lega and Konopka, who have expertly guided my development as an aspiring physician-scientist. The training plan in place for this fellowship period will allow me to learn and develop innovative skills for studying human brain tissue in vitro with a combination of electrophysiology, molecular biology, and genomic approaches. Benefitting from the unique combination of expertise from my mentors and the resources provided by UTSW, this training will allow me to grow as a rigorous, passionate physician-scientist with the tools to develop novel methods to study and treat the neurological disorders of my patients.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).