Thursday, November 21, 2024 11/21/2024

Integrated Platform for Discovery and Validation of Probes that Restore Protein Expression in Single-Gene Causes of Autism and Related Disorders

Award Number: R01MH113648
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Drug discovery pipelines for neuropsychiatric disorders are dry. One approach to rejuvenating these pipelines would be to create assays based on relevant disease phenotypes in primary neurons, something that is currently lacking. However, a scalable assay development platform that is based on bona fide neurons, remains cost effective, and that can support industrial level high-throughput screening (HTS) does not currently exist. Over the past eight years (spread across different NIH-sponsored grants), our collaborative group has created a flexible and scalable primary neuron-based assay development system that is compatible with industrial-level HTS. Our long-standing goal for this project has been to optimize these procedures and workflows to support neuron-based HTS phenotypic assays so that they can support very large screening campaigns of up to 200K compounds. We are happy to report that progress over the last budget period has pushed us closer toward this stated goal. We have invented a state-of-the-art, disease-modeling assay created in primary neurons that is designed to discover compounds that reverse the cellular consequences of genetic haploinsufficiency. Indeed, a substantial proportion of childhood brain disorders are caused by single autosomal dominant variants resulting in genetic haploinsufficiency. The rare genetic brain disorders that arise from these variants offer great potential for translation because the disease mechanism is well-understood (i.e. low protein expression). Therefore, a rationale precision therapy for treating genetic haploinsufficiency disorders would be to discover “magic bullet” compounds that raise expression of functional proteins from the remaining undamaged allele (e.g. “boosting compounds”). In this renewal project, we will employ technical innovations that have unlocked the scalability of primary neurons for phenotypic HTS. As a proof-of-principle, we will scale-up and implement an assay that reports reversal of low SynGAP expression in neurons caused by genetic haploinsufficiency of the SYNGAP1/Syngap1 gene. We will miniaturize an HTS-compatible and disease- modeling steady-state endogenous SynGAP expression assay so that it is compatible with industrial scale HTS automation. Once implemented, we will then screen up to 200,000 unique substances using a completely automated version of the neuron-based SynGAP expression assay. Finally, using a comprehensive multi-stage biological validation funnel, we will identify and prioritize the most translatable chemical probes that raise SynGAP protein expression. The overall impact of this project is that discovery of multiple, validated SynGAP boosting compounds would provide proof-of-principle that our flexible platform is an effective tool for phenotypic drug discovery for nervous system disorders.


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: 2024 ( Subtotal = -$5,890 )
2024	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Mental Health Research Grants	000	8	6/18/2024	NON-COMPETING CONTINUATION	-$5,890
														Subtotal = -$5,890

Issue Date FY: 2023 ( Subtotal = $774,212 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Mental Health Research Grants	002	8	3/24/2023	NON-COMPETING CONTINUATION	$774,212
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Mental Health Research Grants	001	7	1/3/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$222,113
2023	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	000	6	1/3/2023	NON-COMPETING CONTINUATION	-$222,113
														Subtotal = $774,212

Issue Date FY: 2022 ( Subtotal = $842,868 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Mental Health Research Grants	003	7	5/17/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$23,091
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	001	6	4/26/2022	NON-COMPETING CONTINUATION	-$483,666
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Mental Health Research Grants	002	7	4/27/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$570,264
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	000	6	2/7/2022	NON-COMPETING CONTINUATION	$779,361
														Subtotal = $842,868

Issue Date FY: 2021 ( Subtotal = $652,164 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	000	5	3/12/2021	NON-COMPETING CONTINUATION	$652,164
2021	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	002	4	6/12/2021	COMPETING CONTINUATION	$30,699
2021	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	001	3	6/12/2021	NON-COMPETING CONTINUATION	-$30,699
														Subtotal = $652,164

Issue Date FY: 2020 ( Subtotal = $668,094 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	001	4	4/30/2020	COMPETING CONTINUATION	$668,094
2020	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	000	3	4/23/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $668,094

Issue Date FY: 2019 ( Subtotal = $686,767 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	000	3	3/13/2019	NON-COMPETING CONTINUATION	$686,767
														Subtotal = $686,767

Issue Date FY: 2018 ( Subtotal = $555,274 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	000	2	3/16/2018	NON-COMPETING CONTINUATION	$499,746
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	001	2	6/15/2018	NON-COMPETING CONTINUATION	$55,528
														Subtotal = $555,274

Issue Date FY: 2017 ( Subtotal = $687,348 )
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	000	1	6/21/2017	NEW	$687,348
														Subtotal = $687,348

Grand Total All Awards = $4,860,837

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Integrated Platform for Discovery and Validation of Probes that Restore Protein Expression in Single-Gene Causes of Autism and Related Disorders

Award Number: R01MH113648

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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