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Small molecule induced proteolytic destruction of intrinsically disordered proteins

Award Number: R01AG066223
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2019
PERIOD OF PERFORMANCE END DATE: 01/10/2024

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Small molecule induced proteolytic destruction of intrinsically disordered proteins - The significance: There are still no effective treatments for Alzheimer’s disease and Alzheimer’s disease related dementias. The problem: The pathogenesis of Alzheimer’s disease is driven in large part by the toxic signaling of amassed intrinsically disordered proteins (IDPs), such tau, which has a high tendency to aggregate upon accumulation. In addition to its tendency to aggregate upon accumulation, these unfolded IDPs lack defined binding pockets, thus they have largely evaded traditional drug discovery design efforts and are often deemed “undruggable”. During healthy homeostasis, IDPs are short-lived and in low-to-undetectable quantity, because IDPs are unremittingly proteolytically degraded by the 20S proteasome. However, when IDP production outpaces its degradation (due to gene amplification, mutation or other cellular dysfunctions including a decrease in proteasome function), their subsequent accumulation can lead to harmful signaling. Of all human organs and tissues, the brain expresses one of the highest levels of IDPs, and over-expression of certain IDPs have been directly linked to these neurodegenerative disorders. The solution: Recent ground breaking studies found that enhancing proteasome activity can prevent toxic accumulation of IDPs, reduce brain damage and prevent dementia. Our approach: Our hypothesis is that we can reduce toxic levels of over-expressed IDPs by enhancing/restoring 20S proteasomal degradation using small molecules. Instead of inhibiting IDPs with a drug, we will induce their proteolytic destruction by developing small molecules that enhance 20S proteasome activity. This approach is different from all previous attempts to target IDP-instigated diseases. Consistent with the low-to-undetectable levels of IDPs during healthy homeostasis, we found that enhancing 20S proteasome-mediated proteolysis has a minimal effect on normal cellular functions. This is an unexplored field in science and human health and we will be one of the first to determine the possibilities and limitations of this new approach in this work.


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 = -$24,912 )
2024	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	001	4	4/19/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	002	4	4/19/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	004	4	5/14/2024	SUPPLEMENT FOR EXPANSION	-$7,059
2024	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	003	4	5/14/2024	NON-COMPETING CONTINUATION	-$17,853
2024	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	000	4	4/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = -$24,912

Issue Date FY: 2022 ( Subtotal = $511,982 )
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	002	4	5/17/2022	NON-COMPETING CONTINUATION	$366,910
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	004	3	8/18/2022	SUPPLEMENT FOR EXPANSION	-$26,413
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	001	3	12/10/2021	SUPPLEMENT FOR EXPANSION	$26,413
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	000	3	11/16/2021	SUPPLEMENT FOR EXPANSION	$34,307
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	003	4	5/18/2022	SUPPLEMENT FOR EXPANSION	$53,583
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	006	4	8/20/2022	SUPPLEMENT FOR EXPANSION	$53,583
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	005	4	8/19/2022	SUPPLEMENT FOR EXPANSION	$3,599
														Subtotal = $511,982

Issue Date FY: 2021 ( Subtotal = $446,428 )
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	001	3	5/12/2021	NON-COMPETING CONTINUATION	$428,566
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	000	2	2/19/2021	SUPPLEMENT FOR EXPANSION	$17,862
														Subtotal = $446,428

Issue Date FY: 2020 ( Subtotal = $368,746 )
2020	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	000	2	8/10/2020	NON-COMPETING CONTINUATION	$368,746
														Subtotal = $368,746

Issue Date FY: 2019 ( Subtotal = $369,612 )
2019	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	000	1	9/8/2019	NEW	$369,612
														Subtotal = $369,612

Grand Total All Awards = $1,671,856

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Small molecule induced proteolytic destruction of intrinsically disordered proteins

Award Number: R01AG066223

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2019

PERIOD OF PERFORMANCE END DATE: 01/10/2024

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