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Novel Protein Aggregation Inhibitors and Upper Motor Neuron Stabilizers for ALS and other Neurodegenerative Diseases

Award Number: R01AG061708
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 09/29/2024

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Novel Protein Aggregation Inhibitors and Upper Motor Neuron Stabilizers for ALS and other Neurodegenerative Diseases - Abstract: Recent developments in chemistry, genetics, and biology revealed that many of the age-related neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and ALS/FTD share protein accumulation as the common cause of neuropathology. In addition, the number and kinds of compounds generated within the last years have exponentially increased. However, these developments in science have not yet successfully translated into effective drug discoveries for patients. This proposal is a collaborative project between the Silverman and Ozdinler Labs, blending expertise in medicinal chemistry and selective neuronal vulnerability, respectively. In an effort to expedite drug discovery and to identify novel compounds that can move into clinical trials for ALS and age-related disorders, which develop in part because of protein aggregation, such as Alzheimer's disease, we have developed a novel strategy and a strong team effort. This strategy also could, more broadly, ameliorate other neurodegenerative diseases in which voluntary movement is affected and in which protein aggregation is a major underlying cause. Dr. Silverman discovered several compounds that inhibit protein aggregation in cells and that have favorable pharmacokinetic properties, and Dr. Ozdinler developed a novel in vitro and in vivo preclinical drug screening/verification platform using the improved health of upper motor neurons (UMNs) that become diseased from different underlying factors, as the read-out. Recent discoveries from the Ozdinler group reveal the importance of improving UMN health early in the disease and that maintaining UMN health is crucial for effective drug discovery efforts. It is unfortunate that this important neuron population has never before been considered in preclinical studies, even for diseases that are identified by their selective and progressive degeneration. This proposal will develop the first preclinical platform that utilizes diseased UMNs for the assessment of novel compounds generated in the Silverman lab that inhibit protein aggregation and improve the health of diseased UMNs both in vitro and in vivo. Upon completion of this proposal, we will move the field forward along two different avenues by developing a new preclinical assay that incorporates UMN health as the read-out, and by identifying novel drugs for age-related neurodegenerative diseases that develop from problems with protein aggregation .


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	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	000	6	11/13/2024	COMPETING CONTINUATION	$0
2025	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	001	5	2/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,536,774 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	001	6	9/19/2024	COMPETING CONTINUATION	$1,536,774
2024	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	000	5	9/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,536,774

Issue Date FY: 2023 ( Subtotal = $561,194 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	000	5	4/27/2023	NON-COMPETING CONTINUATION	$561,194
														Subtotal = $561,194

Issue Date FY: 2022 ( Subtotal = $609,584 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	000	4	5/18/2022	NON-COMPETING CONTINUATION	$609,584
														Subtotal = $609,584

Issue Date FY: 2021 ( Subtotal = $742,539 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	001	3	8/11/2021	SUPPLEMENT FOR EXPANSION	$120,000
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	000	3	5/11/2021	NON-COMPETING CONTINUATION	$622,539
														Subtotal = $742,539

Issue Date FY: 2020 ( Subtotal = $635,495 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	000	2	4/20/2020	NON-COMPETING CONTINUATION	$635,495
														Subtotal = $635,495

Issue Date FY: 2019 ( Subtotal = $671,753 )
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	001	1	8/10/2019	NEW	$45,800
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	000	1	7/26/2019	NEW	$625,953
														Subtotal = $671,753

Grand Total All Awards = $4,757,339

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Novel Protein Aggregation Inhibitors and Upper Motor Neuron Stabilizers for ALS and other Neurodegenerative Diseases

Award Number: R01AG061708

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 09/29/2024

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