Two scientists from UCLA’s David Geffen School of Medicine received nearly $ 10 million from the National Institutes of Health’s Brain research through the advancement of innovative neurotechnologies® (BRAIN) Initiative for research projects aiming to shed light on the cellular infrastructure of the developing brain to better understand brain disorders.
Chongyuan Luo, an assistant professor of human genetics, for the first time received a grant totaling approximately $ 5.3 million over five years to systematically map the gene regulation landscape through human brain development with single-cell resolution. . Aparna Bhaduri, an assistant professor of biological chemistry, will receive approximately $ 4.3 million over five years through a UCSF-led project to examine genetic activity and structure in developmental and cross-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.
Grant of Luo: Scientists hypothesized that many psychiatric disorders result from impaired brain development, which is supported by observations that genetic variants associated with a variety of neuropsychiatric disorders are enriched in genomic regions active during brain development. However, the causal brain structure or cell type for mental disorders is often unknown, making it difficult to develop treatments for psychiatric disorders.
Through the use of two cutting-edge single-cell technologies, Luo’s research team will map the regulatory regions of genes to understand how 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 test developed by 10x Genomics to characterize regions of gene regulation.
The effort will enable researchers to build a comprehensive catalog of cell types in the developing brain and identify regions of gene regulation at a cell-type-specific level for hundreds of brain cell types.
The database will significantly enhance our study of genetic variants associated with psychiatric and neurological disorders. More specifically, the dataset can lead to the discovery of specific cell types and genomic regions that mediate the 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 the Luo project is U01MH130995-01.
Grant of Bhaduri: His project is part of a $ 36.4 million grant from UCSF to examine brain development in humans, macaques and marmosets during 4 stages of development: peak neurogenesis before birth, immediately after birth. birth, childhood and adolescence. The project aims to establish which cell types exist in the brains of human and non-human primates, how they change over time and how they are organized in space. The species comparison will help researchers understand which types of brain cells may be the most unique in humans and thus may be more vulnerable to disease.
“With these responses we can then better understand how the brain is normally developed and how it is affected by neurodevelopmental and neuropsychiatric disorders,” said Bhaduri.
Bhaduri likened the effort to generate a “parts list” of the developing human brain using relatively new technology that allows researchers to effectively construct a detailed map. Researchers will use single-cell RNA sequencing to study genes activated by single cells and at the same time use single-cell ATAC sequencing to examine genome architecture. This will help generate fundamental guidance for cell types through development and, in parallel, researchers will examine cells in their spatial landscape in the brain.
The project builds on previous work by Bhaduri and colleagues who examined the development of the human cortex, which allows for complex cognition, and many other brain structures in the early stages of development.
The grant covers researchers from several institutions, including: Arnold Kriegstein, Tomasz Nowakowski and Alex Pollen of UCSF; Nenad Sestan and Rong Fan of Yale University; Huang Hao of the University of Pennsylvania; Jon Levine and Andre Sousa of the University of Wisconsin-Madison; and Marcel Daadi of the Texas Biomedical Research Institute. The license number is 1UM1MH130991-01.
“With the announcement of the BICAN Awards, we are making an exciting transition into the BRAIN Initiative’s overall cell census program, which began in 2014,” said Dr. John Ngai, Director of the NIH BRAIN Initiative. “These awards will enable researchers to explore the multifaceted characteristics of the more than 200 billion neurons and non-neuronal cells in the human brain in unprecedented detail and size; a feat in advanced technologies and research collaboration between teams that will reveal new paradigms for understanding. as pathological changes in particular groups of brain cells could cause neurological and neuropsychiatric disorders “.
University of California – Los Angeles Health Sciences