Dr. Muhle is a practicing child psychiatrist with a strong track record of developing molecular and genetic tools to elucidate the mechanism of disease. The long-term goal of this career development award is to identify regulatory networks underlying autism spectrum disorder (ASD) through the integration of state-of-the- art functional genomics, single cell transcriptomics, and systems biology analyses with precision-engineered models of early brain development. She initiated this project during her time in the Adult and Child Psychiatry Research Training Program at the Yale Child Study Center, with the mentorship of James Noonan, Ph.D. and co-mentorship of Matthew State, M.D., Ph.D. With the guidance of Dr. Noonan, a world-wide leader in using functional genomics to understand development and evolution, and the support of Dr. State, an undisputed pioneer and leader in ASD genetics, Dr. Muhle developed expertise in regulatory genomics and the genetic architecture of ASD. Her career goal is to become an independent investigator, examining the role of the ASD risk gene Chromodomain Helicase DNA-binding Protein 8 (CHD8) in the development of ASD. Her research goal is to determine the role of CHD8 and the impact of its loss on regulatory networks. Our hypothesis is that CHD8 regulates ASD risk-associated networks in specific cell-types that become dysregulated when CHD8 expression is altered. To address these questions, she successfully generated a Chd8 constitutive knockout mouse and an Avi-tagged Chd8 mouse that she will use to identify Chd8-regulated networks in specific cell-types at high cellular resolution. She also proposes a high-throughput small molecule screen to explore potential upstream developmental signaling pathways that effect CHD8-regulated expression networks. The following independent specific aims will address our hypothesis: 1) Determine cell-type specific expression changes due to Chd8 haploinsufficiency in the developing cortex. 2) Map Chd8-bound cell-type specific regulatory networks at high resolution in the cortex. 3) Identify bioactive modulators of CHD8 expression networks via high-throughput reporter assay. Our rationale is that by studying CHD8, a key regulatory molecule that targets other ASD risk genes, we will expand our knowledge of other ASD risk genes and identify CHD8-targeted regulatory networks in particular cell-types to further define the biology of ASD. With the continued mentorship of Dr. Noonan and co-mentorship of Marina Picciotto, M.D., an expert in animal models of neurobehavioral disorders, with collaboration of Thomas Fernandez, M.D., a child psychiatrist with expertise in systems analyses of genetic risk factors, and Smita Krishnaswamy, Ph.D., a computational biologist on the cutting-edge of statistical and mathematical modeling, Dr. Muhle will develop the experimental and analytical skills necessary to fully utilize the model systems she has developed. Together with the resources of the Yale Child Study Center and her career development goals, she will attain her career goal to illuminate basic biological mechanisms underlying brain development and risk for ASD.
Autism spectrum disorder (ASD) is a highly prevalent congenital disorder most often characterized by life-long impairments in social communication that create significant obstacles to education, employment and formation of relationships. There is a significant public health need for therapeutics that target the core symptoms of ASD, but despite recent foundational advances in understanding genetic contributors to ASD etiology there is a gap in our understanding of how the diverse etiologies of ASD converge into common pathways on a molecular and cellular level. The studies proposed in this application combine cutting-edge functional genomics and single cell transcriptomics with novel animal and cellular models of early brain development to identify regulatory networks of genes and pathways associated with autism risk at unprecedented cellular resolution, which will provide new-found insight into the biological underpinnings of ASD pathology to inform the development of novel, targeted therapeutics.
