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Integrative Network Biology Approaches to Identify, Characterize and Validate Molecular Subtypes in Alzheimer's Disease

Award Number: U01AG046170
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Alzheimer's disease (AD) pathology is characterized by the presence of phosphorylated tau in neurofibrillary tangles (NFTs), dystrophic neurites and abundant extracellular ß-amyloid in senile plaques. However, the etiology of AD remains elusive, partly due to the wide spectrum of clinical and neurobiological/neuropathological features in AD patients. Thus, heterogeneity in AD has complicated the task of discovering disease-modifying treatments and developing accurate in vivo indices for diagnosis and clinical prognosis. Different approaches have been proposed for AD subtyping, but they are generally neither suitable for high-dimensional data nor actionable due to the lack of mechanistic insights. Increased knowledge and understanding of different AD subtypes would shed light on recently failed clinical trials and provide for the potential to tailor treatments with specificity to more homogeneous subgroups of patients. By integrating genetic, molecular and neuroimaging data to more precisely define AD subtypes, we may be able to better discriminate between highly overlapping clinical phenotypes. Furthermore, the identification of such subtypes may potentially improve our understanding of its underlying pathomechanisms, prediction of its course, and the development of novel disease-modifying treatments. In this application, we propose to systematically identify and characterize molecular subtypes of AD by developing and employing cutting-edge network biology approaches to multiple existing large-scale genetic, gene expression, proteomic and functional MRI datasets. We will investigate the functional roles of key drivers underlying predicted AD subtypes as well as three candidate key drivers from our current AMP-AD consortia work in control and AD hiPSC-derived neural co-culture systems and then in complex organoids by screening the predicted transcriptional impact of top key drivers in single cell and cell-population-wide analyses. Functional assays in each cell type will be used to build evidence for relevance to AD-subtype phenotypes. Single cell RNA sequencing data will be generated to identify perturbation signatures in selected drivers that will then be mapped to subtype specific networks to build comprehensive signaling maps for each driver. The top three most promising drivers of AD subtypes and the three existing AMP-AD targets will be further validated using a) an independent postmortem cohort, and b) recombinant mice, including amyloidosis, tauopathy and new “humanized” models.


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 = $0 )
2023	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	10	9/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $2,691,623 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	9	12/2/2021	SUPPLEMENT FOR EXPANSION	$419,201
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	002	10	8/26/2022	NON-COMPETING CONTINUATION	$2,272,422
2022	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	001	9	4/25/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,691,623

Issue Date FY: 2021 ( Subtotal = $2,017,540 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	8	6/18/2021	SUPPLEMENT FOR EXPANSION	$169,500
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	001	9	8/25/2021	NON-COMPETING CONTINUATION	$1,848,040
														Subtotal = $2,017,540

Issue Date FY: 2020 ( Subtotal = $4,545,053 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	004	7	4/27/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	001	7	3/17/2020	SUPPLEMENT FOR EXPANSION	$164,076
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	002	7	3/31/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	005	8	9/1/2020	NON-COMPETING CONTINUATION	$3,115,604
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	003	7	4/8/2020	SUPPLEMENT FOR EXPANSION	$1,265,373
2020	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	7	11/15/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $4,545,053

Issue Date FY: 2019 ( Subtotal = $2,115,045 )
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	003	7	8/31/2019	NON-COMPETING CONTINUATION	$1,691,295
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	004	7	9/12/2019	SUPPLEMENT FOR EXPANSION	$423,750
2019	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	002	6	7/25/2019	COMPETING CONTINUATION	$450,319
2019	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	6	1/8/2019	COMPETING CONTINUATION	$0
2019	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	001	5	7/25/2019	NON-COMPETING CONTINUATION	-$450,319
														Subtotal = $2,115,045

Issue Date FY: 2018 ( Subtotal = $1,708,836 )
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	002	6	9/20/2018	COMPETING CONTINUATION	$1,708,836
2018	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	5	7/5/2018	NON-COMPETING CONTINUATION	$0
2018	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	001	5	9/19/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,708,836

Issue Date FY: 2017 ( Subtotal = $2,868,507 )
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	005	5	8/18/2017	NON-COMPETING CONTINUATION	$2,699,009
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	004	4	6/29/2017	SUPPLEMENT FOR EXPANSION	$169,498
2017	2016	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	003	4	1/31/2017	EXTENSION WITH OR WITHOUT FUNDS	$214,286
2017	2015	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	002	3	1/31/2017	SUPPLEMENT FOR EXPANSION	-$111,000
2017	2015	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	3	1/31/2017	NON-COMPETING CONTINUATION	-$6,951
2017	2015	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	001	3	1/31/2017	SUPPLEMENT FOR EXPANSION	-$96,335
														Subtotal = $2,868,507

Issue Date FY: 2016 ( Subtotal = $4,588,807 )
2016	2016	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	001	4	8/26/2016	EXTENSION WITH OR WITHOUT FUNDS	$3,281,179
2016	2016	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	000	3	5/31/2016	SUPPLEMENT FOR EXPANSION	$1,139,520
2016	2016	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	002	4	9/5/2016	SUPPLEMENT FOR EXPANSION	$168,108
														Subtotal = $4,588,807

Issue Date FY: 2015 ( Subtotal = $1,910,159 )
2015	2015	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	000	3	8/21/2015	NON-COMPETING CONTINUATION	$1,702,824
2015	2015	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	002	3	9/7/2015	SUPPLEMENT FOR EXPANSION	$96,335
2015	2015	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	001	3	8/29/2015	SUPPLEMENT FOR EXPANSION	$111,000
														Subtotal = $1,910,159

Issue Date FY: 2014 ( Subtotal = $1,848,805 )
2014	2014	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	000	1	5/9/2014	SUPPLEMENT FOR EXPANSION	$114,059
2014	2014	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	001	2	9/5/2014	NON-COMPETING CONTINUATION	$1,734,746
														Subtotal = $1,848,805

Issue Date FY: 2013 ( Subtotal = $1,659,748 )
2013	2013	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	000	1	9/17/2013	NEW	$1,659,748
														Subtotal = $1,659,748

Grand Total All Awards = $25,954,123

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Integrative Network Biology Approaches to Identify, Characterize and Validate Molecular Subtypes in Alzheimer's Disease

Award Number: U01AG046170

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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