Tuesday, May 13, 2025 5/13/2025

Endophenotype Network-based Approaches to Prediction and Population-based Validation of in Silico Drug Repurposing for Alzheimers Disease

Award Number: R01AG066707
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Endophenotype Network-based Approaches to Prediction and Population-based Validation of in Silico Drug Repurposing for Alzheimers Disease - Although researchers have conducted more than 400 human trials for potential treatments of Alzheimer’s disease (AD) in the last two decades, the attrition rate is estimated at over 99%. Furthermore, the “one gene, one drug, one disease” reductionism-informed paradigm overlooks the inherent complexity of the disease and continues to challenge drug discovery for AD. The predisposition to AD involves a complex, polygenic, and pleiotropic genetic architecture. Recent studies have suggested that AD often has common underlying mechanisms, sharing intermediate endophenotypes with many other complex diseases. These endophenotypes, such as amyloidosis and tauopathy, have essential roles in many neurodegenerative diseases. Systematic identification and characterization of novel underlying pathogenesis and disease modules, more so than mutated genes, will serve as a foundation for generating actionable targets as input for drug repurposing and rational design of combination therapy in AD. Integration of the genome, transcriptome, proteome, and the human interactome are essential for such identification. Given our preliminary results, we posit that network- based identification of novel risk genes and endophenotype modules that share degree between amyloid and tau offer unexpected opportunities for drug therapy in AD comparing to targeting amyloid and tau separately. To address the underlying hypothesis, we propose to establish an integrated interdisciplinary research plan with three specific aims. Aim 1 will explore amyloid and tau-mediated endophenotype modules for AD -- We will test the network module hypothesis for amyloid and tau using our recently developed Bayesian framework that integrates multi-omics data (i.e., genome-wide association studies [GWAS] loci, single cell sequencing, and human brain Hi-C data) and the human interactome. Aim 2 will be capable of searching existing drugs and combination therapies for AD using network proximity approaches -- We will emphasize the uses of network proximity approaches (i.e., Genome-wide Positioning Systems network [GPSnet]) to identify repurposable drugs and efficacious combination regimens. This will be accomplished by integrating AD endophenotype module findings, public drug-target databases, the human interactome, and the large-scale patient longitudinal Claims- Electronic Medical Record data (over 200 million patients from the MarketScan database). Aim 3 will evaluate brain penetration and target network engagement for repurposable drugs -- We will use the humanized in vitro blood-brain barrier, resected brain tissues (ex vivo/in situ), and transgenic AD models (i.e., TgF344-AD rats) to experimentally evaluate brain penetration and target network engagement. Evaluation will be based upon network proximity to the AD-related endophenotype modules that are relevant to maximizing efficacy and to minimizing side effects. The successful completion of this project will offer powerful network methodologies and bioinformatics tools for prediction and population-based validation of in silico drug repurposing. It will also allow for the identification of novel repurposable drugs and clinically relevant combination therapies toward AD trials.


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: 2025 ( Subtotal = $0 )
2025	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	001	5	5/2/2025	NON-COMPETING CONTINUATION	$199,496
2025	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	5	4/28/2025	NON-COMPETING CONTINUATION	-$199,496
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $591,820 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	5	1/18/2024	NON-COMPETING CONTINUATION	$532,638
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	001	5	6/4/2024	NON-COMPETING CONTINUATION	$59,182
														Subtotal = $591,820

Issue Date FY: 2023 ( Subtotal = $721,981 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	4	1/26/2023	NON-COMPETING CONTINUATION	$721,981
														Subtotal = $721,981

Issue Date FY: 2022 ( Subtotal = $771,366 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	001	3	5/3/2022	NON-COMPETING CONTINUATION	$77,138
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	3	2/8/2022	NON-COMPETING CONTINUATION	$694,228
														Subtotal = $771,366

Issue Date FY: 2021 ( Subtotal = $985,720 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	002	2	2/3/2021	NON-COMPETING CONTINUATION	$663,720
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Trans-NIH Research Support	003	2	8/31/2021	SUPPLEMENT FOR EXPANSION	$322,000
2021	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	001	1	2/1/2021	NEW	$0
2021	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	1	11/17/2020	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $985,720

Issue Date FY: 2020 ( Subtotal = $1,030,564 )
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	1	4/2/2020	NEW	$634,650
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	002	1	9/2/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	001	1	8/31/2020	SUPPLEMENT FOR EXPANSION	$395,914
														Subtotal = $1,030,564

Grand Total All Awards = $4,101,451

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Endophenotype Network-based Approaches to Prediction and Population-based Validation of in Silico Drug Repurposing for Alzheimers Disease

Award Number: R01AG066707

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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Department of Health & Human Services

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Award Information

Endophenotype Network-based Approaches to Prediction and Population-based Validation of in Silico Drug Repurposing for Alzheimers Disease

Award Number: R01AG066707

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer

Endophenotype Network-based Approaches to Prediction and Population-based Validation of in Silico Drug Repurposing for Alzheimers Disease