UCLA scientists receive $10 million to shed light on the developing brain’s cellular infrastructure


Two scientists from the David Geffen School of Medicine at UCLA have been awarded nearly $10 million by the National Institutes of Health Brain research through the further development of innovative neurotechnologies® (BRAIN) Initiative for research projects aimed at shedding light on the cellular infrastructure of the developing brain to better understand brain diseases.

Chongyuan Luo, an assistant professor of human genetics, received a grant totaling about $5.3 million over five years to systematically map the gene regulatory landscape in human brain development at a single-cell resolution for the first time. Aparna Bhaduri, an assistant professor of biological chemistry, will receive about $4.3 million over five years through a UCSF-led project to study genetic activity and structure across developmental stages and species.

The NIH grants were awarded through the agency’s BRAIN Initiative Cell Atlas Network (BICAN), a large-scale effort to comprehensively catalog cell types and molecular properties in the brain.

Luo’s scholarship: Scientists have hypothesized that many psychiatric disorders result from impaired brain development, supported by observations that genetic variants associated with a variety of neuropsychiatric disorders are enriched in genomic regions that are active during brain development. However, the causal brain structure or cell type for psychiatric disorders is often unknown, making the development of treatments for psychiatric disorders difficult.

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Using two state-of-the-art single-cell technologies, Luo’s research team will map gene regulatory regions to understand how the associated genetic variants affect brain development. The first, sn-m3C-seq (PMID: 31501549), simultaneously profiles DNA methylation and three-dimensional chromatin architecture in the same cell. The second, snmCT-seq (PMID: 35419551), jointly profiles DNA methylation and gene expression from the same cell. The research team will also use a droplet-based single-cell chromatin accessibility assay developed by 10x Genomics to characterize gene regulatory regions.

The effort will allow researchers to create a comprehensive catalog of cell types in the developing brain and identify gene regulatory regions at the cell-type-specific level for hundreds of brain cell types.

The database will greatly enhance our study of genetic variants associated with psychiatric and neurological disorders. More specifically, the dataset may lead to the discovery of specific cell types and genomic regions that mediate risk of brain disease.”


Chongyuan Luo, Assistant Professor of Human Genetics

Luo’s team will collaborate with research groups led by Jason Ernst at UCLA, Mercedes Paredes and Tomasz Nowakowski at UCSF, and Eran Mukamel at UCSD. The grant number for Luo’s project is U01MH130995-01.

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Bhaduri’s scholarship: Her project is part of a $36.4 million UCSF grant to study brain development in humans, macaques and marmosets at 4 developmental stages: peak neurogenesis before birth, immediately after birth, childhood and adolescence. The aim of the project is to find out what cell types exist in the human and non-human primate brain, how they change over time and how they are spatially organized. The comparison between the species will help researchers understand which brain cell types may be more unique in humans and therefore more susceptible to disease.

“With these answers, we can then better understand how the brain normally develops and how it is affected by neurodevelopmental and neuropsychiatric disorders,” Bhaduri said.

Bhaduri likened the effort to creating a “parts list” of the developing human brain through the use of relatively new technology that allows researchers to effectively create a detailed map. The researchers will use single-cell RNA sequencing to study genes that are turned on by single cells, and at the same time they will use single-cell ATAC sequencing to study genome architecture. This will help create a crucial guide to cell types during development, and in parallel assays, researchers will study the cells in their spatial landscape in the brain.

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The project builds on previous work by Bhaduri and colleagues, which studied the developing human cortex, which enables complex cognition, and several other brain structures in early development.

The grant includes researchers at multiple institutions, including: Arnold Kriegstein, Tomasz Nowakowski, and Alex Pollen of UCSF; Nenad Sestan and Rong Fan from Yale University; Huang Hao from the University of Pennsylvania; Jon Levine and Andre Sousa from the University of Wisconsin-Madison; and Marcel Daadi of the Texas Biomedical Research Institute. The grant number is 1UM1MH130991-01.

“With the announcement of the BICAN awards, we are making an exciting transition in the overall BRAIN initiative cell counting program that began in 2014,” said Dr. John Ngai, Director of the NIH BRAIN Initiative. “These awards will enable researchers to explore the multifaceted properties of more than 200 billion neurons and non-neuronal cells in the human brain in unprecedented detail and scale – a feat of advanced technology and cross-team research collaboration that will unveil new paradigms to… understand how pathological changes in specific groups of brain cells can cause neurological and neuropsychiatric disorders.”

Source:

University of California – Los Angeles Health Sciences



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