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Mechanisms of Novel Regulators of Proteotoxicity and Quality Control Associated with ALS/FTD

Award Number: R01NS074324
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2011
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Mechanisms of Novel Regulators of Proteotoxicity and Quality Control Associated with ALS/FTD - Project Summary Neurodegeneration is an increasing public health challenge and remains an unsolved biomedical problem. Protein misfolding and aggregation are a central feature of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The complexity of neurodegeneration calls for large-scale unbiased screening studies. Over the past few years, we have made breakthrough observations with significant implications for understanding the cellular defense systems against proteotoxicity underlying pathogenesis in ALS/FTD. Using a unique blend of genetic, biochemical, and cell biological approaches, we have uncovered novel pathways that enable reprogramming of protein quality control to counter proteotoxicity. The newly proposed work in this project is aimed at elucidating mechanisms underlying newly identified regulators and master switches in protein quality control. The studies on the previously unrecognized higher-order regulators could expand our understanding of proteotoxic-stress-responsive quality control systems in the cell, beyond the well-established heat shock response or unfolded protein response. Our unique abilities to contribute to this field are at both conceptual and technical levels: In additional to novel pathways, we have developed unique C. elegans/mammalian reporter systems to study proteotoxicity-associated neurodegeneration, and our recent success bodes well for future plans. Furthermore, our expanding repertoire of tools will allow us to extend the findings to diverse models and patient cells. The specific aims are to elucidate the mechanisms through which a novel conserved pathway, involving a previously unknown transcriptional master switch, in the regulation of protein quality control, to delineate the pathways through which a novel target and its signaling pathway regulate proteotoxicity, and to develop new tools for more advanced search for key regulators of proteotoxicity and quality control. The findings will not only provide novel entry points for understanding the toxicities of key ALS/FTD proteins, such as SOD1, TDP-43, and C9orf72 DPRs, but also reveal molecular targets for harnessing the cellular defense system to prevent and treat the relevant neurodegenerative diseases. We predict that the advances gained through our research efforts will eventually lead to new therapeutic interventions to address these diseases in the world’s rapidly aging population.


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 = $470,466 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	2/20/2025	NON-COMPETING CONTINUATION	$470,466
														Subtotal = $470,466

Issue Date FY: 2024 ( Subtotal = $530,927 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	14	4/9/2024	NON-COMPETING CONTINUATION	$53,092
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	14	9/16/2024	NON-COMPETING CONTINUATION	$0
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	1/22/2024	NON-COMPETING CONTINUATION	$477,835
														Subtotal = $530,927

Issue Date FY: 2023 ( Subtotal = $530,927 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	2/22/2023	NON-COMPETING CONTINUATION	$530,927
														Subtotal = $530,927

Issue Date FY: 2022 ( Subtotal = $537,477 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	2/4/2022	NON-COMPETING CONTINUATION	$483,728
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	12	3/28/2022	NON-COMPETING CONTINUATION	$53,749
														Subtotal = $537,477

Issue Date FY: 2021 ( Subtotal = $537,477 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	1/22/2021	COMPETING CONTINUATION	$537,477
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	11	8/22/2021	COMPETING CONTINUATION	$21,598
2021	2020	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	8/22/2021	NON-COMPETING CONTINUATION	-$21,598
														Subtotal = $537,477

Issue Date FY: 2020 ( Subtotal = $364,973 )
2020	2020	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	2/26/2020	NON-COMPETING CONTINUATION	$364,973
														Subtotal = $364,973

Issue Date FY: 2019 ( Subtotal = $343,679 )
2019	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	1/31/2019	NON-COMPETING CONTINUATION	$364,973
2019	2018	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	12/10/2018	NON-COMPETING CONTINUATION	-$21,294
														Subtotal = $343,679

Issue Date FY: 2018 ( Subtotal = $441,148 )
2018	2018	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	1/22/2018	NON-COMPETING CONTINUATION	$397,033
2018	2018	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	4/26/2018	NON-COMPETING CONTINUATION	$44,115
														Subtotal = $441,148

Issue Date FY: 2017 ( Subtotal = $473,216 )
2017	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	7	5/26/2017	NON-COMPETING CONTINUATION	$35,631
2017	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	2/27/2017	NON-COMPETING CONTINUATION	$410,575
2017	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	1/23/2017	SUPPLEMENT FOR EXPANSION	$15,172
2017	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	4/19/2017	NON-COMPETING CONTINUATION	$9,991
2017	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	4/19/2017	SUPPLEMENT FOR EXPANSION	$1,847
														Subtotal = $473,216

Issue Date FY: 2016 ( Subtotal = $364,973 )
2016	2016	JOHNS HOPKINS UNIVERSITY	1101 E 33RD STREET, STE-C-210	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	5/26/2016	COMPETING CONTINUATION	$364,973
2016	2015	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/24/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $364,973

Issue Date FY: 2015 ( Subtotal = $322,875 )
2015	2015	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/24/2015	NON-COMPETING CONTINUATION	$322,875
														Subtotal = $322,875

Issue Date FY: 2014 ( Subtotal = $319,646 )
2014	2014	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/28/2014	NON-COMPETING CONTINUATION	$319,646
														Subtotal = $319,646

Issue Date FY: 2013 ( Subtotal = $311,574 )
2013	2013	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/24/2013	NON-COMPETING CONTINUATION	$20,986
2013	2013	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/12/2013	NON-COMPETING CONTINUATION	$290,588
														Subtotal = $311,574

Issue Date FY: 2012 ( Subtotal = $322,875 )
2012	2012	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/26/2012	NON-COMPETING CONTINUATION	$322,875
														Subtotal = $322,875

Issue Date FY: 2011 ( Subtotal = $322,875 )
2011	2011	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/8/2011	NEW	$322,875
														Subtotal = $322,875

Grand Total All Awards = $6,195,108

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Mechanisms of Novel Regulators of Proteotoxicity and Quality Control Associated with ALS/FTD

Award Number: R01NS074324

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2011

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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