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Exploring Mechanisms of Pathogenicity in C9ORF72 Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Award Number: R00AG057808
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Exploring Mechanisms of Pathogenicity in C9ORF72 Frontotemporal Dementia and Amyotrophic Lateral Sclerosis - Project Summary/Abstract Age-related neurodegenerative disorders represent a major financial and emotional burden to society, but to date no preventative strategies have been developed. Frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS) are relentlessly progressive diseases which involve the degeneration of neurons important for behavior and muscle movement, respectively. A hexanucleotide repeat expansion in a non-protein-coding region of the gene C9ORF72 was recently discovered to be the most common cause of FTD and ALS, responsible for 10% of all diagnoses. Two prevailing hypotheses have been suggested to explain how this mutation leads to progressive loss of neurons. The gain of function (GOF) hypothesis proposes that toxic molecules produced from the repeat expansion disrupt neural function and lead to their destruction. The loss of function (LOF) hypothesis proposes that the C9ORF72 protein plays an important role in support of neural function and survival and that reduced expression of this gene directly or indirectly sensitizes neurons to disease. New evidence indicates that the mouse ortholog of C9ORF72 functions in the immune system to limit inflammation and autoimmunity, although the exact mechanisms require further study. The first AIM of this proposal will be to identify pathways and cell types that contribute to inflammation when the C9ORF72 ortholog is reduced and to determine whether induced pluripotent stem cell-derived microglia-like cells from humans with the C9ORF72 repeat expansion display similar inflammatory phenotypes. The second AIM of this proposal seeks to test the validity of the LOF hypothesis in live organisms by injecting virus containing the hexanucleotide repeat expansion into mice that express normal or reduced levels of the C9ORF72 ortholog. If lower levels of the C9ORF72 ortholog sensitize animals to toxic features of the repeat expansion, this would provide support for developing therapies aimed at boosting levels of C9ORF72 or inhibiting pathways affected by its reduction. The candidate will train with experts in diverse fields to develop the technical skills necessary to complete these AIMs and to identify disease relevant pathways which can be pursued in the independent phase of this proposal. Continued training with the candidate’s advisor and expert collaborators will prepare him to succeed in his goal to run an independent research group in which he mentors investigators of all levels and pursues hypotheses aimed at understanding etiologies of neurodegenerative disease.


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 = -$193 )
2025	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	000	5	10/9/2024	NON-COMPETING CONTINUATION	-$193
														Subtotal = -$193

Issue Date FY: 2023 ( Subtotal = $248,999 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	000	5	3/15/2023	NON-COMPETING CONTINUATION	$248,999
														Subtotal = $248,999

Issue Date FY: 2022 ( Subtotal = $248,999 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	000	4	3/31/2022	NON-COMPETING CONTINUATION	$248,999
														Subtotal = $248,999

Issue Date FY: 2021 ( Subtotal = $248,999 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	000	3	6/23/2021	EXTENSION WITH OR WITHOUT FUNDS	$248,999
														Subtotal = $248,999

Grand Total All Awards = $746,804

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Exploring Mechanisms of Pathogenicity in C9ORF72 Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Award Number: R00AG057808

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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