[R01] Noncoding RNAs in Neurodevelopmental Disorders
Ente: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Scadenza: 2031-07-31
Importo max: 709.408 EUR
Paese: US
Descrizione
Project Summary/Abstract
The goal of this project is to determine the functions of long noncoding RNAs (lncRNAs) that contribute to
neurodevelopmental disorders. We have published that the first two genome wide association studies (GWAS)
of autism spectrum disorder (ASD) implicated lncRNAs as the functional elements. We showed that the
lncRNA MSNP1AS was the functional element revealed by the first published ASD GWAS peak on
chromosome 5p14.1 and that the lncRNA RPS10P2-AS1 was a functional element revealed by the second
ASD GWAS peak on chromosome 20p12.1. Both of the GWAS peaks have been replicated. Both of the
lncRNAs are over-expressed in postmortem cerebral cortex of individuals with ASD and the genome-wide
associated allele was correlated with increased expression in postmortem cerebral cortex. We published that
over-expression of each of these lncRNAs in human neural progenitor cells causes changes in gene
expression and neuronal morphology. The changes in gene expression were enriched in pathways of
chromatin structure and protein synthesis. Together with similar gene network analyses of rare mutations,
these data suggest a convergence on these biological processes in ASD risk. While we focused specifically on
identifying the functional elements of GWAS hits, publications from other groups have used genetic and gene
expression data to hypothesize that more than 1,200 lncRNAs are implicated in neurodevelopmental disorders.
These hypothesis-generating studies provide convincing statistical evidence but do not provide experimental
evidence that any of the lncRNAs are functional in developing human brain. Therefore, we propose to test the
function of 10 high confidence lncRNAs by manipulating expression in human cerebral organoids. Aim 1 will
identify the gene networks regulated by each lncRNA in both human postmortem cerebral cortex and human
cerebral organoids. Aim 2 will use endogenous RNA pull down to determine the direct binding interactions of
each of the 10 lncRNAs. Aim 3 will measure altered neuronal differentiation, synaptic function, and social
behavior caused by manipulation of each lncRNA. These data will begin to fill the knowledge gap of the
molecular and cellular functions of lncRNAs that have been implicated in neurodevelopmental disorders. The
proposed experiments will provide both validation and mechanistic insight into the lncRNAs implicated in
neurodevelopmental disorders.
Istituzione: HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES
PI: Daniel Brian Campbell
Progetto: 1R01HD118985-01A1
Settori: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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