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Higher Order Chromatin and Genetic Risk for Schizophrenia

Award Number: R01MH106056
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2015
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Higher Order Chromatin and Genetic Risk for Schizophrenia - The large majority of genomic loci linked to schizophrenia heritability by genome-wide association harbor regulatory non-coding DNA, including enhancers and repressors, that are not bound to the nearest TSS but instead tethered via chromosomal contacts to genes located elsewhere on the chromosome. Therefore, unsurprisingly, `linear genome' based approaches such as gene expression quantitative trait loci (eQTL) and SNP prioritization algorithms have very limited success in assigning specific target genes to risk loci. Guided by recent Hi-C genome-scale chromosomal contact mapping studies by us and others, we will test in this proposal whether the genetic risk architecture of schizophrenia is associated with cell-type specific vulnerabilities as it pertains to the developmental reorganization of the chromosomal connectome. We predict that neuronal specification into glutamatergic, GABAergic and dopaminergic lineages associated with cell-type specific genome-scale prunings of chromosomal contacts and loss of smaller-scaled chromatin domains. This includes the domain protoype of many of the smaller self-folded `topologically-associated domain' (TAD), with the developmental dissolution of many subTADs nested into larger and megadomain TADs. Furthermore, we predict that differentiating neurons show a disproportionate increase in chromosomal contacts anchored in sequences conferring heritable risk for schizophrenia and related cognitive disorders and traits. We will monitor developmentally regulated shufflings of intranuclear positions for specific GWAS loci and predict mportant differences between the various neural cell types isogenically generated from hiPSCs. If so, then the `functional epistasis', or least co-regulation, of subsets of risk loci sharing the same nuclear sub-territory could be highly dependent on cell type. Last but not least, we predict that targeted mobilization of specific chromatin domains by CRISPR-Genome Organization (CRISPR-GO) approaches can be harnessed for simultaneous targeting of multiple GWAS locis to to specific nuclear compartments such as the nuclear lamina or Cajal body, resulting in multi-layered transcriptome and epigenome changes and cell-type specific phenotypic alterations.


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 = $0 )
2026	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	9	12/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $815,593 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	9	8/7/2023	NON-COMPETING CONTINUATION	$815,593
														Subtotal = $815,593

Issue Date FY: 2022 ( Subtotal = $815,593 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	8	7/28/2022	NON-COMPETING CONTINUATION	$815,593
														Subtotal = $815,593

Issue Date FY: 2021 ( Subtotal = $815,593 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	7	8/12/2021	NON-COMPETING CONTINUATION	$815,593
														Subtotal = $815,593

Issue Date FY: 2020 ( Subtotal = $858,519 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	002	6	8/7/2020	NON-COMPETING CONTINUATION	$858,519
2020	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	5	5/7/2020	COMPETING CONTINUATION	$7,954
2020	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	4	5/7/2020	NON-COMPETING CONTINUATION	-$7,954
														Subtotal = $858,519

Issue Date FY: 2019 ( Subtotal = $888,002 )
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	5	9/24/2019	COMPETING CONTINUATION	$888,002
														Subtotal = $888,002

Issue Date FY: 2018 ( Subtotal = $643,901 )
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	4	6/15/2018	NON-COMPETING CONTINUATION	$64,391
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	4	11/20/2017	NON-COMPETING CONTINUATION	$579,510
														Subtotal = $643,901

Issue Date FY: 2017 ( Subtotal = $644,437 )
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	3	12/9/2016	NON-COMPETING CONTINUATION	$579,993
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	3	5/31/2017	NON-COMPETING CONTINUATION	$64,444
														Subtotal = $644,437

Issue Date FY: 2016 ( Subtotal = $652,734 )
2016	2016	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Mental Health Research Grants	000	2	11/25/2015	NON-COMPETING CONTINUATION	$587,461
2016	2016	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Mental Health Research Grants	001	2	3/15/2016	NON-COMPETING CONTINUATION	$65,273
														Subtotal = $652,734

Issue Date FY: 2015 ( Subtotal = $605,291 )
2015	2015	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Mental Health Research Grants	000	1	1/15/2015	NEW	$605,291
														Subtotal = $605,291

Grand Total All Awards = $6,739,663

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Higher Order Chromatin and Genetic Risk for Schizophrenia

Award Number: R01MH106056

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2015

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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