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The role of autism susceptibility genes in the 16p11.2 locus on the development and function of human stem cell-derived neural cells

Award Number: K99MH119327
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2021

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The role of autism susceptibility genes in the 16p11.2 locus on the development and function of human stem cell-derived neural cells - PROJECT SUMMARY/ABSTRACT Recent reports estimate that 1 out of every 6 children in the United States meet the diagnostic criteria for neurodevelopmental disorders such as autism spectrum disorders (ASD), attention-deficit hyperactivity disorder (ADHD), and intellectual disability (ID). The prevalence of ASDs, which are characterized by persistent social impairments, language deficits, and repetitive behaviors, has increased by 120% over the past 15 years, a problem further exacerbated by the fact that the disease mechanisms underlying ASDs are largely unknown and no targeted therapeutic interventions exist. Recent progress in human genome sequencing has begun to illuminate pathways to disease through the identification of several genetic risk factors, the most common of which is the deletion of 16p11.2 locus (16p11.2del). Initial studies have nominated specific genes in the 16p11.2 locus in neuronal dysfunction, though these findings are built on mouse and zebrafish models rather than human neural cell types. This proposal aims to elucidate the disease mechanisms underlying 16p11.2del phenotypes using in vitro induced pluripotent stem cell (iPSC)-derived human brain cells. In Aim 1 (K99), human iPSC- derived neural progenitor cells and neurons generated using novel protocols will be compared to human fetal brain tissue using single-cell RNA sequencing (scRNA-seq) techniques to validate these in vitro cellular models for future studies. Aim 2 of this proposal (K99) will employ an innovative “population-in-a-dish” strategy in which stem cell lines from many different neurotypical and 16p11.2del patients will be pooled into one culture flask to interrogate phenotypic differences. Aim 3 (R00) will leverage these scRNA-seq techniques to decipher the role of 16p11.2 genes in specific pathways important for neurodevelopment. The successful completion of these aims could lead to the identification of genetic targets for therapeutic intervention, while also dramatically changing the way the field conducts in vitro modeling of human brain disorders. These experiments will provide new training for the principal investigator (PI) of this proposal in scRNA-seq and bioinformatics methods that will serve as the foundation of an independent research laboratory that will use stem cell-derived neural cells and large transcriptome datasets, combined with animal models, to elucidate the cellular and molecular mechanisms governing neurodevelopmental disorders. This work will be completed at the Broad Institute and Harvard University, where the opportunities for technical and intellectual growth are innumerable. The PI will attend regular meetings with mentors and collaborators to receive feedback on experimental design and career decisions. The PI will attend grant writing and project management courses at Harvard, while also improving his communication skills by presenting data at international scientific conferences. As a whole, this career development plan will help the PI establish his own group at a research-oriented academic institution and become a leader in the field of neurodevelopmental disease modeling.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$696 )
2023	2021	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Mental Health Research Grants	000	2	11/22/2022	SUPPLEMENT FOR EXPANSION	-$696
														Subtotal = -$696

Issue Date FY: 2021 ( Subtotal = $22,590 )
2021	2021	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Mental Health Research Grants	001	2	5/28/2021	SUPPLEMENT FOR EXPANSION	$22,590
2021	2020	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Mental Health Research Grants	000	2	5/27/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $22,590

Issue Date FY: 2020 ( Subtotal = $102,330 )
2020	2020	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Mental Health Research Grants	000	2	6/10/2020	NON-COMPETING CONTINUATION	$102,330
														Subtotal = $102,330

Issue Date FY: 2019 ( Subtotal = $102,330 )
2019	2019	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Mental Health Research Grants	000	1	4/29/2019	NEW	$102,330
														Subtotal = $102,330

Grand Total All Awards = $226,554

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The role of autism susceptibility genes in the 16p11.2 locus on the development and function of human stem cell-derived neural cells

Award Number: K99MH119327

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2021

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