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Dysregulation of autophagy-lysosomal function links TBI to late-onset neurodegeneration

Award Number: R01NS115876
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: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Dysregulation of autophagy-lysosomal function links TBI to late-onset neurodegeneration - PROJECT SUMMARY Epidemiological data link history of traumatic brain injury (TBI) to increased likelihood of development of Alzheimer’s Disease (AD) and other AD-related dementias (ADRD) later in life. While recent meta-analyses estimate the overall risk of dementia attributable to TBI at 5-15%, it remains poorly understood how history of brain trauma may contribute to neurodegeneration years or even decades later. One possibility is that TBI may accelerate detrimental cellular changes occurring during normal brain ageing. A potential candidate is the autophagy-lysosomal pathway essential for degrading misfolded proteins and damaged organelles. Autophagy function declines during brain aging and more severely in neurodegenerative diseases. Thus, accelerated inhibition of autophagy-lysosomal function as compared to that observed in normal brain aging, could contribute to neurodegeneration observed in AD and other age-related dementias. We recently demonstrated that autophagy is also inhibited after TBI. This is caused by TBI-induced lysosomal defects and is associated with profound changes in lysosomal lipid composition. Lysosomal dysfunction associated with accumulation of lipofuscin and other lipid byproducts in the endo-lysosomal compartments is also observed in aged mice and is exacerbated by either drug or disease induced demyelinating episodes. Since TBI leads to myelin damage as well as more general perturbation of lipid metabolism in the brain, lipid-mediated damage could also lead to lysosomal inhibition after TBI and over time cause accelerated autophagy-lysosomal dysfunction as compared to that observed during normal aging, thus contributing to AD/ADRD. We hypothesize that perturbation of lipid homeostasis after TBI accelerates lysosomal lipid accumulation as compared to normal aging, leading to lysosomal dysfunction and autophagy defects, thus predisposing to neurodegeneration and AD/ADRD. In order to test this hypothesis, we will use HILIC-MS/MS based lipidomic analysis of brain lysosomes, MS-based lipid imaging and complementary IF/IHC and biochemical approaches to compare changes in lysosomal lipid composition and autophagy-lysosomal function in the brains of normal aging mice and mice aging after TBI. To test the causative effect of perturbed autophagy and lipid metabolism on development of AD/ADRD relevant pathological and cognitive phenotypes we will use autophagy hypomorph Becn1+/- mice and Scarb1+/- mice with hypercholesterolemia. We will also use a fly TBI model to identify additional autophagy and lipid metabolism genes linking TBI to AD/ADRD. We expect that our data will demonstrate that perturbation of lysosomal lipid metabolism and autophagy by TBI is an important contributor to subsequent development of AD/ADRD.


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 = $602,129 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/2/2024	NON-COMPETING CONTINUATION	$602,129
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	9/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $602,129

Issue Date FY: 2023 ( Subtotal = $602,129 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/20/2023	NON-COMPETING CONTINUATION	$602,129
														Subtotal = $602,129

Issue Date FY: 2022 ( Subtotal = $602,129 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/20/2022	NON-COMPETING CONTINUATION	$602,129
														Subtotal = $602,129

Issue Date FY: 2021 ( Subtotal = $652,128 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/7/2021	NON-COMPETING CONTINUATION	$652,128
														Subtotal = $652,128

Issue Date FY: 2020 ( Subtotal = $611,411 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	3/24/2020	NEW	$104,612
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/11/2020	NEW	$506,799
														Subtotal = $611,411

Grand Total All Awards = $3,069,926

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Dysregulation of autophagy-lysosomal function links TBI to late-onset neurodegeneration

Award Number: R01NS115876

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: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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