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Characterizing patient-specific TBR1 mutations: Understanding a master regulator of autism risk

Award Number: R01MH113926
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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Characterizing patient-specific TBR1 mutations: Understanding a master regulator of autism risk - PROJECT SUMMARY/ABSTRACT Over the past decade, genetic studies focused on identifying de novo mutations have unlocked ~100-200 new mid to high-confidence autism risk genes. These mutations are likely highly penetrant and provide a biologic handle to begin clarifying the molecular, cellular, and circuit level changes that define autism risk. However, our ability to understand how mutations in these genes disrupt brain development has not kept pace with this peri- od of rapid risk gene discovery. Network analysis approaches have identified a convergence of highly inter- connected autism risk genes that begin to function during human midfetal stages of development in glutama- tergic cortical neurons—pointing to a possible network or pathway that defines a more general autism etiology. The most connected gene in the deep layer developmental network is TBR1, suggesting it is a master regula- tor. TBR1 is a high-confidence autism risk gene that codes for a neuronal transcription factor. To investigate the impact of TBR1 mutations, novel mouse lines have been generated that mimic three major classes of re- ported patient mutations, including early-frameshift, T-box missense, and late-frameshift mutations. Published and preliminary studies comparing the brains of these patient mimic lines and the original Tbr1 two-exon dele- tion line have shown shared as well as distinct phenotypes. Intriguingly, all heterozygous mutation mice share a thinning of the axon bundles of the anterior commissure, which has also now been observed in human pa- tients. However, despite these advances, the precise impact of different TBR1 patient mutations on neurode- velopmental trajectories across brain regions and cell-types remains unknown. Thus, there is a critical need to identify the key molecular mechanisms, dosage-sensitive network targets, cell-types, and developmental win- dows impacted by TBR1 mutations. Failing to define these impacts prevents our understanding of TBR1- associated autism and the larger network defined by the convergence of many autism risk genes. The overall objectives of this project are to: Aim 1) Discover the critical cell-types and developmental windows impacted by TBR1 mutations in vivo and how they compare to in vitro models of human corticogenesis by leveraging single- cell genomics; and Aim 2) Determine the shared and distinct synaptic deficits in patient mutation mouse lines that impact behavior and evaluate the potential of postnatally rescuing function using viral tracing/optogenetics, ex vivo physiology, and autism-relevant behavioral paradigms. This multimodal approach will rigorously assess the impact of three major classes of TBR1 mutations on molecular, cellular, synaptic, and behavioral pheno- types. These results are expected to have an important positive impact as they will provide an unprecedented view into the mechanistic consequences of TBR1 mutations on neuronal development and the TBR1-regulated network associated with autism risk genes. By defining key principles of TBR1 dysfunction, this work will inform therapeutic strategies for TBR1-associated autism as well as for convergent mechanisms driving autism risk.


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: 2026 ( Subtotal = $786,439 )
2026	2026	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Mental Health Research Grants	000	6	3/19/2026	COMPETING CONTINUATION	$786,439
														Subtotal = $786,439

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Mental Health Research Grants	000	5	2/2/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $250,786 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Mental Health Research Grants	000	5	6/29/2022	SUPPLEMENT FOR EXPANSION	$250,786
2022	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Mental Health Research Grants	001	5	8/26/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $250,786

Issue Date FY: 2021 ( Subtotal = $499,244 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Mental Health Research Grants	000	5	5/26/2021	NON-COMPETING CONTINUATION	$499,244
														Subtotal = $499,244

Issue Date FY: 2020 ( Subtotal = $499,244 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Mental Health Research Grants	000	4	5/15/2020	NON-COMPETING CONTINUATION	$499,244
														Subtotal = $499,244

Issue Date FY: 2019 ( Subtotal = $499,244 )
2019	2019	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Mental Health Research Grants	000	3	5/14/2019	NON-COMPETING CONTINUATION	$499,244
														Subtotal = $499,244

Issue Date FY: 2018 ( Subtotal = $499,244 )
2018	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Mental Health Research Grants	000	2	5/14/2018	NON-COMPETING CONTINUATION	$499,244
														Subtotal = $499,244

Issue Date FY: 2017 ( Subtotal = $499,244 )
2017	2017	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Mental Health Research Grants	000	1	8/25/2017	NEW	$499,244
														Subtotal = $499,244

Grand Total All Awards = $3,533,445

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Characterizing patient-specific TBR1 mutations: Understanding a master regulator of autism risk

Award Number: R01MH113926

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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