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Novel SETD5-based Molecular Mechanisms and Therapeutic Tools to Understand and Revert Neuronal Dysfunction Associated with Intellectual disability and Autism

Award Number: R01MH127077
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/05/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Novel SETD5-based Molecular Mechanisms and Therapeutic Tools to Understand and Revert Neuronal Dysfunction Associated with Intellectual disability and Autism - PROJECT SUMMARY Autism spectrum disorder (ASD), which is usually accompanied of intellectual disability (ID), is part of a group of neurodevelopmental disorders that are usually diagnosed during the first two years of age. The social, emotional and communication skills of affected individuals are severely impaired throughout life and are often accompanied by a spectrum of debilitating symptoms with different degrees of severity including, stereotypic behavioral traits, epileptic episodes, sensory oversensitivity, and impaired motor functions that seriously interfere with their daily life activities. ASD is an important public health concern as it affects 1 in 54 individuals. It occurs in all racial, ethnic, and socioeconomic groups, and in the United States alone, the estimated total cost per year per children is between $11.5 and $60.9 billion. Thus, families with ID/ASD-diagnosed children experience heavy psychological and financial burdens. While early intervention services can significantly improve certain aspects of child's development, no disease-modifying treatments are currently available. Despite enormous efforts, lack of effective therapies is likely due to our poor understanding of the molecular and cellular mechanisms underlying these conditions with exceedingly complex etiology. The number of different types of genetic variations associated with ASD keeps increasing thanks to the improvement in genomic sequencing technology. However, there is still little understanding of how these genetic changes impact cellular and molecular pathways or which brain cell are more affected by these mutations that ultimately result in brain dysfunction associated with ASD. Among them, loss-of-function genetic variations in the SETD5 gene, which is believe to play an important role in the structure of the genome and in regulating expression of neuronal genes. However, there are important knowledge gaps on the molecular and cellular pathways controlled by SETD5 and how ASD-related mutations in this gene could contribute to neuronal dysfunction. We and others started to address these questions by generating Setd5 deficient mice and showed impaired neuronal function and appearance of ASD-like behaviors. However, mouse models are limited to accurately recapitulate not only disease pathologies but also the protracted process of human brain development. Thus, they can lead to misleading hypothesis. To compensate for these limitations, we have modeled for the first time SETD5-related ASD using human induced pluripotent stem cells (hiPSC). Generating neurons from these cells we recapitulated neuronal dysfunction as previously observed in mice models. More importantly, we uncovered new mechanisms inducing this neuronal dysfunction. In particular, we found that astrocytes, which are more abundant and necessary for keeping neurons healthy and connected in the brain, might produce neurotoxic activity. In this proposal, we extensively characterize the molecular and cellular pathways involved in this process and explore novel therapeutic targets to revert or prevent neuronal dysfunction induced by SETD5 mutations. The successful completion of this research will provide an unprecedented view of astrocyte involvement in ASD and potentially revolutionize its treatment.


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: 2027 ( Subtotal = $0 )
2027	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	5	10/16/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $778,227 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	5	1/21/2026	NON-COMPETING CONTINUATION	$778,227
														Subtotal = $778,227

Issue Date FY: 2025 ( Subtotal = $781,258 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	001	4	8/14/2025	NON-COMPETING CONTINUATION	$117,189
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	4	1/28/2025	NON-COMPETING CONTINUATION	$664,069
														Subtotal = $781,258

Issue Date FY: 2024 ( Subtotal = $784,231 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	3	1/12/2024	NON-COMPETING CONTINUATION	$705,807
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	001	3	8/14/2024	NON-COMPETING CONTINUATION	$78,424
														Subtotal = $784,231

Issue Date FY: 2023 ( Subtotal = $787,147 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	2	1/18/2023	NON-COMPETING CONTINUATION	$787,147
														Subtotal = $787,147

Issue Date FY: 2022 ( Subtotal = $789,998 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	001	1	6/27/2022	NEW	$79,001
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	1	3/5/2022	NEW	$710,997
														Subtotal = $789,998

Grand Total All Awards = $3,920,861

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Novel SETD5-based Molecular Mechanisms and Therapeutic Tools to Understand and Revert Neuronal Dysfunction Associated with Intellectual disability and Autism

Award Number: R01MH127077

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/05/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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