[K99] Integration of spatial and multi-ome data to characterize molecular and cellular networks in ASD

Ente: National Institute of Mental Health

Scadenza: 2028-08-31

Importo max: $118,476

Paese: US

Descrizione

Project Summary The long-term goal of this K99/R00 application is to develop Dr. Lucy Bicks’s capacity to successfully conduct studies linking molecular cascades of Neurodevelopment Disorders in postmortem brain with the early developmental sequelae to understand the emergence of the molecular phenotype underlying these disorders, especially Autism Spectrum Disorder (ASD). In the K99 phase, the proposed project supports Dr. Bicks in four major training areas that will allow her to transition to an independent investigator who uses both primary source tissue, single cell transcriptomic, epigenomic, and spatial tools, genetic interrogation methods, and developmental models to understand how the developmental axis contributes to the cellular changes seen in ASD. First, Dr. Bicks will extend her knowledge of single cell technologies used in postmortem brain to create single cell gene expression and ‘multi-ome’ libraries from human postmortem brain. Second, she will deepen her knowledge of network methods to understand molecular cascades in single cell systems by learning several tools to derive the major regulators of transcriptional change by linking single cell read outs with regulatory networks and genetic liability. Third, she will learn a new technique, high-throughput single molecular imaging to be able to add a new dimension to ‘omics’ research – the spatial dimension at nearly transcriptome-wide breadth. Through this she will learn not only the molecular biology of this technique, she will also learn the analytic methods to derive novel information with the spatial axis of ASD molecular endophenotypes. Finally, Lucy will learn to grow and maintain both human cortical and human thalamic organoids, and will learn to use these organoid models to examine the causal implications of changes in regulatory networks seen in the postmortem brain. The four research aims of this project mirror Lucy’s training aims. First, in Aim 1 she will create multi-omic single cell libraries across the cortical lobes in ASD brain and she will use these transcriptomic and epigenomic libraries to understand transcription factor regulatory networks that coordinate gene and pathway changes in the ASD cortex. Aim 2 takes a similar approach but for the first time examines single cell thalamic nuclei changes and connects them with cortical changes. Aim 3 will examine the spatial axis, interrogating changes in the ASD brain at the very local level to understand how micro cellular environments can help us to understand the bigger picture of ASD brain changes. Aim 4 will allow Lucy to learn the organoid developmental model systems and test the causal effects of the transcription factors on their downstream regulatory targets in a developmental model system. The proposed research works towards closing the gap between developmental models that examine early changes, usually focusing specifically on a handful of genes causally associated with ASD, and molecular endophenotypes see Istituzione: UNIVERSITY OF CALIFORNIA LOS ANGELES PI: Lucy Bicks Progetto: 1K99MH141252-01A1

Settori: National Institute of Mental Health

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