Dup15q Alliance is excited to present the 2017-2019 Dup15q Alliance Fellowship winner.
Vidya is a second year Neuroscience PhD student in Dr. Shafali Jeste’s lab and her research focuses on understanding the mechanisms underlying EEG biomarkers in the Duplication 15q (Dup15q) Syndrome. Before joining the Jeste lab, Vidya worked in the laboratory of Dr. Theo Palmer in Stanford University where she studied the effects of maternal immune activation as well as GABA receptor deficiency on placental function and fetal brain development. Using genetic mouse models of autism, she investigated mechanisms underlying gestational immune challenges that lead to later life dysfunctions in neurodevelopmental disorders including autism. Vidya graduated with a Master of Engineering degree in Biotechnology from the Birla Institute of Technology and Science (BITS) in India. After college, she was hired by Histogenetics LLC, New York, a pioneer in HLA typing research where she worked as a Genetic Researcher, before moving to California.
Project Title: Evaluating A Scalable EEG Biomarker In Dup15q Syndrome
Project Dates: 10/1/2017-9/30/2019
Annual grant: $25,000
Identifying biomarkers of genetic disorders with well-defined etiology like duplications of 15q11.2-13.1 (Dup15q syndrome), not only offers us the opportunity to understand the underlying biology of atypical brain development but also enables early diagnosis, prognosis, and aids in developing treatment-targets. A unique electrophysiological (EEG) signature in the form of increased beta oscillations distinguishes individuals with Dup15q syndrome from those without the syndrome . Since this EEG signature resembles the pattern induced by gamma-aminobutyric acid alpha subunit (GABAA) receptor modulation and the 15q11.2-13.1 regions include GABAA receptor genes, beta oscillations may reflect the underlying genetic abnormality in Dup15q syndrome and may be extremely valuable as a biomarker in pharmacological interventions that modulate GABAA receptors. In order to successfully move forward with a clinical trial and utilize this biomarker as a marker of target-engagement and outcome, it is critical to understand the relationship between this biomarker and clinical profiles. The overall goals of this grant are to 1) quantify beta oscillations in routine clinical EEGs of a large and heterogeneous population of children with Dup15q syndrome from clinics across the country; 2) examine the clinical correlates of beta power; and 3) determine if beta oscillations inhibit state-dependent modulation of neural activity and whether a lack of neuromodulation affects sleep architecture and correlates with developmental outcomes. Quantifying this biomarker across the whole Dup15q population is critical in both exploring syndrome-specific mechanisms and in validating beta oscillations as a highly penetrant and clinically relevant biomarker that can ultimately inform clinical response to pharmacologic intervention.
James Fink received his Ph.D. from the University of Connecticut Health Center where he worked in the laboratory of Dr. Eric Levine. While in the Levine lab, James used induced pluripotent stem cell (iPSC) -derived neurons from patients with Angelman and Dup15q syndromes to study the intrinsic function of individual neurons and the synaptic connectivity and plasticity between neurons as a way of identifying cellular phenotypes associated with these neurodevelopmental disorders. A large portion of his Ph.D. research was funded by a Dup15q Alliance training fellowship aimed at investigating hyperexcitable behavior in neurons from Dup15q patients. Using patch-clamp electrophysiology, James has patched ~10,000 iPSC-derived neurons, establishing 20 to 30-week maturation profiles of neuronal function, while also uncovering significant differences across a variety of functional parameters in both Angelman and Dup15q neurons. He is now a Senior Scientist in the Cell Biology department at Q-State Biosciences in Cambridge, MA. Q-State’s all-optical electrophysiology platform, which is capable of functional measurements from >100,000 individual neurons per day, is several orders of magnitude higher throughput compared to manual patch clamp. Combining this platform with iPSC-derived neurons provides unprecedented insight into patient disease-associated functional impairments in human neurons in a high-throughput screening manner. At Q-State, James continues to work very closely on a variety of neurodevelopmental disorders and is also involved in guiding efforts to improve synaptic maturation and signaling of iPSC-derived neurons.
Project Title: Hyperexcitability in Human Stem Cell-Derived Neurons From 15q Duplication Syndrome Patients
Project Dates: 10/1/2015-9/30/2018
Annual grant: $25,000
Abstract: Patients with chromosome 15q duplication syndrome (Dup15q) commonly present with impairments in language development, cognition, motor skills, muscle tone, and seizures. Additionally, many patients meet the criteria for autism spectrum disorder (ASD). Though ~50% of patients experience some form of seizure during their lifetime, these seizures remain hard to treat and the cellular mechanisms underlying seizures and other symptoms of Dup15q are unclear. In this study we are using induced-pluripotent stem cell (iPSC) technology, a technique that allows skin cells of individual patients to be converted into stem cells that can then be used to make brain cells (neurons). We have gathered preliminary data that suggests that neurons derived from Dup15q patients have increased activity, which could contribute to the seizures and other symptoms observed in Dup15q. This proposal aims at studying several aspects of neuron function related to seizure production in iPSC-derived neurons from Dup15q patients and identifying underlying molecular mechanisms. This research will be done at the University of Connecticut Health Center, an institution at the forefront of stem cell research with training programs related to neurodevelopmental disorders through collaboration with Connecticut Children’s Medical Center. Through the training that I will receive I hope to further develop as a scientist, learning and mastering new techniques, applying these techniques to important questions, and communicating this research through writing manuscripts and presenting data at scientific conferences. Perhaps most importantly, this research is directly relevant to individuals with Dup15q syndrome as it may identify new cellular targets for drug treatment.
Kevin obtained his BA in behavioral neuroscience from Western Washington University in 2013, and recently in May 2019 completed his doctorate at The University of Tennessee Health Science Center in the lab of Dr. Lawrence Reiter. Kevin’s thesis work focused on identifying the cell types in the brain that may be contributing to Dup15q epilepsy. Additionally, the Drosophila melanogaster (fruit fly) seizure model they developed is being used to identify drugs that may help treat seizure in Dup15q.
Project Title: Investigation of Synergistic Interactions Among Genes in the 15q Duplication Syndrome
Project Dates: 10/1/2015-9/30/2019
Annual grant: $25,000
Abstract: Duplications of the 15q11.2-q13.1 chromosomal region result in Dup15q syndrome. Characteristics of Dup15q include cognitive impairments, autism associated phenotypes, and seizures. Duplication of the ubiquitin ligase UBE3A is thought to cause many of the features of Dup15q including autism, however, several other genes are duplicated in this region as well including GABA receptor genes and another ubiquitin ligase, HERC2, previously demonstrated to interact with UBE3A. The contribution of each of these genes to the phenotypes observed in individuals with Dup15q syndrome remains unexplored and may reveal new approaches to the treatment of aspects of the disorder like sleep problems, seizures and even autism. In this proposal we will utilize Drosophila melanogaster to over-express single genes and combinations of genes from the Dup15q critical region to establish genetic interactions among these genes and synergistic effects of elevated expression levels of these duplicated genes. We will assay cognition, autism associated phenotypes, sleep and seizures in the fly to determine how the genes in the duplicated region produce Dup15q. This project will ultimately reveal the underlying cross-talk among duplicated genes that cause the various aspects of Dup15q syndrome and provide a starting point for the development of novel therapeutic targets to alleviate symptoms of Dup15q syndrome.