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Cellular and Molecular Analysis of the Psychiatric Risk Gene Transcription Factor 4 (TCF4)

Award Number: R01MH110487
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/02/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Cellular and Molecular Analysis of the Psychiatric Risk Gene Transcription Factor 4 (TCF4) - ASD is a common childhood disorder, which occurs in approximately 3.4 out of every 1,000 children, and requires a lifetime of care that leads to a significant burden for both families and state agencies. Core features of ASD include deficits in socialization, communication and behavior, and can present with other comorbidities such as intellectual disability, epilepsy, anxiety, depression, attention deficits and sleep disorders. The majority of ASD cases are complex and classified as sporadic, having a multitude of factors that combine to produce a disease phenotype; however, approximately 20% of ASD cases are syndromic with a well-established genetic cause. Despite the genetic heterogeneity between different types of syndromic ASD, these disorders display an incredible amount of phenotypic overlap. This overlap may indicate that the causal mutations across disorders, funnel through common molecular pathways during neuronal development, and thus indicate the potential for generalizable treatments. Currently, pharmacotherapies are severely lacking, as no effective pharmacological agents currently exist to treat core ASD symptoms. Therefore, further research into the neurobiology and underlying pathophysiology of ASD is required. In our grant, we propose to model ASD by developing cell and animal models in which the ASD risk gene transcription factor 4 (TCF4) is mutated. TCF4 is associated with a rare neurodevelopmental model called Pitt Hopkins Syndrome (PTHS) that displays autism features. We hope by modeling this disorder we can identify cellular and molecular mechanisms associated with risk for ASD that will eventually lead to the discovery of therapeutic interventions. In Aim 1, we demonstrate that Tcf4 regulates the development of oligodendrocytes (OLs) and mutations in Tcf4 result in hypomyelination. Our preliminary data from a mutant Tcf4 mouse model suggests that Tcf4 regulates the differentiation of oligodendrocyte precursor cells (OPCs) into mature OLs and this leads to a significant decrease in myelination. We propose experiments to identify cellular and molecular mechanism for how Tcf4 regulates OPC differentiation. In Aim 2, we propose experiments to connect Tcf4-dependent hypomyelination to physiological and behavioral deficits by specifically manipulating Tcf4 expression only in the OL-lineage. Moreover, we propose to rescue physiological and behavioral deficits by postnatally reinstating Tcf4 expression only in the OL-lineage to determine if this target rescue of myelination can lead to normalization of physiological and behavioral deficits. In Aim 3, we propose to use PTHS patient-derived induce pluripotent stem cells (IPSCs) to determine if OPC differentiation phenotypes observed in our mouse models translate into human models of disease. Together, these Aims are designed to identify therapeutic targets for the treatment of PTHS and potentially other ASDs.


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 = $636,290 )
2024	2024	THE LIEBER INSTITUTE	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	9	5/22/2024	NON-COMPETING CONTINUATION	$636,290
														Subtotal = $636,290

Issue Date FY: 2023 ( Subtotal = $627,592 )
2023	2023	LIEBER INSTITUTE, INC.	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	8	5/18/2023	NON-COMPETING CONTINUATION	$627,592
														Subtotal = $627,592

Issue Date FY: 2022 ( Subtotal = $636,105 )
2022	2022	LIEBER INSTITUTE, INC.	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	7	6/6/2022	NON-COMPETING CONTINUATION	$636,105
														Subtotal = $636,105

Issue Date FY: 2021 ( Subtotal = $640,414 )
2021	2021	LIEBER INSTITUTE, INC.	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	001	6	5/19/2021	NON-COMPETING CONTINUATION	$640,414
2021	2019	LIEBER INSTITUTE, INC.	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	4	5/18/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $640,414

Issue Date FY: 2020 ( Subtotal = $791,545 )
2020	2020	LIEBER INSTITUTE, INC.	855 N WOLFE ST	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	5	4/15/2020	COMPETING CONTINUATION	$791,545
														Subtotal = $791,545

Issue Date FY: 2019 ( Subtotal = $456,500 )
2019	2019	LIEBER INSTITUTE, INC.	855 N WOLFE ST	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	4	5/20/2019	NON-COMPETING CONTINUATION	$456,500
														Subtotal = $456,500

Issue Date FY: 2018 ( Subtotal = $456,500 )
2018	2018	LIEBER INSTITUTE, INC.	855 N WOLFE ST	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	3	5/31/2018	NON-COMPETING CONTINUATION	$456,500
														Subtotal = $456,500

Issue Date FY: 2017 ( Subtotal = $456,500 )
2017	2017	LIEBER INSTITUTE, INC.	855 N WOLFE ST	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	2	5/18/2017	NON-COMPETING CONTINUATION	$456,500
														Subtotal = $456,500

Issue Date FY: 2016 ( Subtotal = $456,500 )
2016	2016	LIEBER INSTITUTE INC	855 NORTH WOLFE STREET	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	1	9/2/2016	NEW	$456,500
														Subtotal = $456,500

Grand Total All Awards = $5,157,946

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Cellular and Molecular Analysis of the Psychiatric Risk Gene Transcription Factor 4 (TCF4)

Award Number: R01MH110487

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/02/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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