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Epigenetic Influence on Thyroid Hormone Action in the Brain and on Behavior

Award Number: R01MH096050
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/26/2012
PERIOD OF PERFORMANCE END DATE: 10/31/2023

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Epigenetic Influence on Thyroid Hormone Action in the Brain and on Behavior - The etiology of many neurodevelopmental disorders including autism, schizophrenia and attention-deficit hyperactive disorder remains poorly understood. It is accepted that environmental factors may be involved and that the heritability of those conditions is relatively high. Numerous epidemiological and genome-wide association studies in affected populations have identified environmental factors and candidate genes increasing the susceptibility to those conditions. However, those genetic and environmental factors can only account for a small percentage of the clinical cases. This suggests that additional environmental influences remain unidentified, and that the majority of the heritable component of those conditions is of non-genetic origin. We hypothesize that brain overexposure to thyroid hormone during development is an important factor contributing to both the environmental and non-genetic heritable components in the etiology of neurodevelopmental disorders. To test this hypothesis, we will use mouse models with genetic and epigenetic deficiency in DIO3, the main brain determinant controlling thyroid hormone action. In Specific Aim #1, we will determine what are the consequences of allele-specific inactivation of Dio3 globally or specifically in neurons for the brain programs of gene expression, adult brain structure and behavior. In Specific Aim #2, we will profile the fetal and neonatal brain expression and the adult brain structure and behavior of genetically normal mouse descendants of ancestral mice that were exposed to an excess of thyroid hormone during development. We will compare the results of developmental gene expression in different parts of the brain with their adult behavior and with the altered epigenome of exposed ancestors to define which brain developmental programs, brain regions, brain functions, and related neurodevelopmental disorders that are affected by abnormal epigenetic inheritance originated in ancestral overexposure to thyroid hormones. Based on the abnormal regulation of circadian rhythms that is typically associated with neurodevelopmental disorders and is also observed in mice lacking the Dio3 gene, we will identify the molecular and developmental basis by which developmental exposure to thyroid hormone excess leads to the abnormal programming of the circadian clock (Specific Aim #3). We anticipate that our work will greatly advance our understanding of the etiology of complex neurodevelopmental conditions and demonstrate the breakthrough concept that a developmental excess of thyroid hormone influences the susceptibility to those conditions directly in the present generation and indirectly in descendants via epigenetic mechanisms of inheritance.


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 = $0 )
2024	2022	MAINEHEALTH	110 FREE ST	PORTLAND	ME	04101	CUMBERLAND	USA	Mental Health Research Grants	000	11	4/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $389,000 )
2022	2022	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	000	11	10/28/2021	NON-COMPETING CONTINUATION	$350,100
2022	2022	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	001	11	5/11/2022	NON-COMPETING CONTINUATION	$38,900
														Subtotal = $389,000

Issue Date FY: 2021 ( Subtotal = $389,000 )
2021	2021	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	000	10	10/30/2020	NON-COMPETING CONTINUATION	$350,100
2021	2021	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	001	10	4/7/2021	NON-COMPETING CONTINUATION	$38,900
														Subtotal = $389,000

Issue Date FY: 2020 ( Subtotal = $389,000 )
2020	2020	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	000	9	11/5/2019	NON-COMPETING CONTINUATION	$350,100
2020	2020	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	001	9	2/3/2020	NON-COMPETING CONTINUATION	$38,900
														Subtotal = $389,000

Issue Date FY: 2019 ( Subtotal = $389,000 )
2019	2019	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	000	8	10/31/2018	NON-COMPETING CONTINUATION	$389,000
														Subtotal = $389,000

Issue Date FY: 2018 ( Subtotal = $389,000 )
2018	2018	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	003	7	3/27/2018	COMPETING CONTINUATION	$24,698
2018	2018	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	001	7	11/6/2017	COMPETING CONTINUATION	$389,000
2018	2016	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	002	6	3/27/2018	EXTENSION WITH OR WITHOUT FUNDS	-$24,698
2018	2016	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	000	6	10/31/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $389,000

Issue Date FY: 2016 ( Subtotal = $391,250 )
2016	2016	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	000	6	4/19/2016	EXTENSION WITH OR WITHOUT FUNDS	$391,250
														Subtotal = $391,250

Issue Date FY: 2015 ( Subtotal = $391,250 )
2015	2015	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	000	5	5/18/2015	NON-COMPETING CONTINUATION	$391,250
														Subtotal = $391,250

Issue Date FY: 2014 ( Subtotal = $391,250 )
2014	2014	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	000	4	4/28/2014	NON-COMPETING CONTINUATION	$391,250
														Subtotal = $391,250

Issue Date FY: 2013 ( Subtotal = $364,431 )
2013	2013	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	002	3	5/8/2013	NON-COMPETING CONTINUATION	$364,431
2013	2012	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Mental Health Research Grants	000	2	11/19/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$402,419
2013	2012	DARTMOUTH COLLEGE	11 ROPE FERRY ROAD, #6210	HANOVER	NH	03755	GRAFTON	USA	Mental Health Research Grants	001	1	11/19/2012	NEW	-$402,419
														Subtotal = $364,431

Issue Date FY: 2012 ( Subtotal = $402,419 )
2012	2012	DARTMOUTH COLLEGE	11 ROPE FERRY ROAD, #6210	HANOVER	NH	03755	GRAFTON	USA	Mental Health Research Grants	000	1	6/25/2012	NEW	$395,000
2012	2012	DARTMOUTH COLLEGE	11 ROPE FERRY ROAD, #6210	HANOVER	NH	03755	GRAFTON	USA	Mental Health Research Grants	001	1	7/12/2012	NEW	$7,419
														Subtotal = $402,419

Grand Total All Awards = $3,885,600

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Epigenetic Influence on Thyroid Hormone Action in the Brain and on Behavior

Award Number: R01MH096050

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/26/2012

PERIOD OF PERFORMANCE END DATE: 10/31/2023

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