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Leveraging a newly identified EZH1 associated syndrome to explore pharmacological recovery of neurodevelopmental disorders

Award Number: R21HD107592
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Neurodevelopmental disorders (NDDs) are a group of conditions that affect brain development and function often leading to lifelong impairments in motor, language, cognitive and/or social behaviors. Increasing evidence involve chromatin regulation in the pathogenic mechanism of neurodevelopmental disorders (NDDs), such as autism and intellectual disabilities. Importantly, chromatin regulators constitute an attractive group for pharmacological intervention given that most harbor enzymatic activities or well-defined binding domains that can be targeted. The overarching goal of this proposal is to identify and test the therapeutic potential of a novel class of chromatin regulator compounds. In particular our work will be focused on a NDD caused by EZH1 gain of function (GOF) mutations that we have recently identified. EZH1, and its paralogue EZH2, catalyze histone H3 Lysine 27 methylation, a chromatin modification that marks and maintains transcriptional repression. Based on our preliminary data we propose the hypothesis that the NDD in these patients is caused by dysregulation of H3K27 methylation leading to abnormal transcriptional repression of neuronal differentiation genes. Thus, we envision a unique opportunity for pharmacological treatment of this patients using EZH inhibitors. To test this hypothesis, we will dissect cellular and molecular mechanisms affected by EZH1 GOF mutations during neuronal differentiation (Aim 1) and identify EZH1 inhibitors with potential to restore neurodevelopmental defects caused by EZH1 GOF mutations (Aim 2). Results obtained here will serve as a proof of principle for the use of EZH inhibitors to treat NDDs caused by EZH1 GOF mutations and potentially extend their application to other NDDs with altered EZH1/2 and H3K27me3 mediated transcriptional repression.


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 = $223,072 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Child Health and Human Development Extramural Research	000	2	8/17/2023	NON-COMPETING CONTINUATION	$223,072
														Subtotal = $223,072

Issue Date FY: 2022 ( Subtotal = $286,072 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Child Health and Human Development Extramural Research	000	1	8/9/2022	NEW	$286,072
														Subtotal = $286,072

Grand Total All Awards = $509,144

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Leveraging a newly identified EZH1 associated syndrome to explore pharmacological recovery of neurodevelopmental disorders

Award Number: R21HD107592

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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