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Study of cell-type specific Alzheimer's disease genetic variants using a novel bioengineered model of iPSC-derived neural tissue

Award Number: R01AG061838
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Study of cell-type specific Alzheimer's disease genetic variants using a novel bioengineered model of iPSC-derived neural tissue - ABSTRACT Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory impairments and cognitive deterioration. Aging is the major risk factor for AD. Furthermore, increasing evidence indicates that astrocytes and microglia are implicated in the pathogenesis of AD. The ε4 allele of the apolipoprotein E gene (APOE) has been identified as a major risk factor contributing to the pathogenesis of sporadic AD (SAD) in about 15-20% of the cases. APOE is the major apolipoprotein expressed in the human brain primarily by astrocytes and to a lesser extent by microglia, and is involved in cholesterol homeostasis, and regulates A? clearance. Furthermore, genome-wide association studies (GWAS) have identified polymorphisms in genes enriched in microglia (e.g. SORL1, CR1, CD2AP, CD33, TREM2, ABCA7) and astrocytes (e.g. CLU and ABCA7) that increase the risk of developing AD. Recent advances in stem cell technology have allowed the reprogramming of primary cells from human subjects into induced pluripotent stem cells (iPSCs) and their differentiation in neurons, astrocytes and microglia. However, conventional 2D culture systems fail to recapitulate the diversity and maturation of multiple cell types and their interaction under physiological and pathological conditions. To overcome these weaknesses we have developed a novel bioengineered model of iPSC-derived neural tissue. Our silk-collagen protein-based ‘donut’ scaffolds can support compartmentalized, 3D brain-like tissues over a year, without necrosis. This tissue model is highly innovative, supporting the differentiating neurons growth in a donut-shaped porous silk sponge within an optically cleared collagen-filled central region for axon connectivity and synapse formation, that will allow for the first time live in vivo studies (e.g., cell-based electrophysiology, trafficking, synaptic functionality) of an human AD brain-like tissue during ageing (months of cultivation) under controlled experimental conditions. More importantly, the architecture of the scaffolds was optimized to meet the metabolic demand of high-density cell cultures in terms of free diffusion of nutrients and oxygen, a fundamental requisite for long-term cultures and ageing-related studies. Thus, we propose to: 1) Assess genotype-phenotype relationship of AD genetic variants enriched in astrocytes and microglia in patient-derived 3D brain-like cultures; 2) Assess genotype-phenotype relationship of AD genetic variants in vivo after transplantation of patient-derived cells in mice.


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 = $975,889 )
2024	2024	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Aging Research	000	5	6/18/2024	NON-COMPETING CONTINUATION	$975,889
														Subtotal = $975,889

Issue Date FY: 2023 ( Subtotal = $975,889 )
2023	2023	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Aging Research	000	4	5/11/2023	NON-COMPETING CONTINUATION	$975,889
														Subtotal = $975,889

Issue Date FY: 2022 ( Subtotal = $975,889 )
2022	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Aging Research	000	3	5/27/2022	NON-COMPETING CONTINUATION	$975,889
														Subtotal = $975,889

Issue Date FY: 2021 ( Subtotal = $975,889 )
2021	2021	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Aging Research	000	2	4/29/2021	NON-COMPETING CONTINUATION	$975,889
														Subtotal = $975,889

Issue Date FY: 2020 ( Subtotal = $975,889 )
2020	2020	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Aging Research	000	1	4/16/2020	NEW	$975,889
														Subtotal = $975,889

Grand Total All Awards = $4,879,445

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Study of cell-type specific Alzheimer's disease genetic variants using a novel bioengineered model of iPSC-derived neural tissue

Award Number: R01AG061838

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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