Friday, May 3, 2024 5/3/2024

Investigating the role of lipid metabolism in protein aggregation and neurodegenerative disease progression

Award Number: R01NS119897
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

PROJECT SUMMARY Pathogenic protein aggregates are a hallmark neuropathologic finding in many neurodegenerative diseases. Most research has thus far focused on how these pathogenic aggregates are formed. However, little is known about the mechanism by which aggregates spread from cell to cell, a hallmark of neurodegenerative disease progression. Parkinson's disease (PD) is the second most common neurodegenerative disease. Mutations in the gene glucosidase beta acid 1 (GBA), which encodes a lysosomal enzyme producing ceramide, are the strongest genetic risk factor for PD. Recently, GBA mutations were also found to associate with accelerated cognitive and motor symptom progression, suggesting that GBA mutations influence the spread of protein aggregates within the brain. Recent work in PD and other neurodegenerative diseases suggest that dysregulation of lipid metabolism, and in particular ceramide, also has an important role in pathogenesis. Our recent work revealed a novel function for GBA in regulating extracellular vesicle (EVs) formation and cargo. I hypothesize that GBA deficiency mediates faster propagation of protein aggregates from cell to cell through dysregulation of EVs. To investigate the mechanisms by which GBA mutations influence the propagation of protein aggregates between tissues and between cells, I will use Drosophila, mouse and human neuronal cell culture models of GBA deficiency. I hypothesize that decreased ceramide levels due to GBA deficiency lead to dysregulation of EVs, which promotes the transfer of protein aggregates from cell to cell and leads to faster progression of neurodegeneration. Understanding the mechanisms underlying the prion-like propagation of protein aggregates has the potential to reveal novel therapeutic targets that could slow or halt PD and other neurodegenerative diseases characterized by the spread of pathogenic 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: 2024 ( Subtotal = $343,371 )
2024	2024	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/23/2024	NON-COMPETING CONTINUATION	$24,779
2024	2024	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/20/2023	NON-COMPETING CONTINUATION	$318,592
														Subtotal = $343,371

Issue Date FY: 2023 ( Subtotal = $416,660 )
2023	2023	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	1/31/2023	NON-COMPETING CONTINUATION	$41,664
2023	2023	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/14/2022	NON-COMPETING CONTINUATION	$374,996
														Subtotal = $416,660

Issue Date FY: 2022 ( Subtotal = $413,294 )
2022	2022	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/3/2021	NON-COMPETING CONTINUATION	$371,966
2022	2022	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/24/2022	NON-COMPETING CONTINUATION	$41,328
														Subtotal = $413,294

Issue Date FY: 2021 ( Subtotal = $465,135 )
2021	2021	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/26/2020	NEW	$425,300
2021	2021	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	6/9/2021	SUPPLEMENT FOR EXPANSION	$39,835
														Subtotal = $465,135

Grand Total All Awards = $1,638,460

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Investigating the role of lipid metabolism in protein aggregation and neurodegenerative disease progression

Award Number: R01NS119897

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer