Saturday, August 2, 2025 8/2/2025

Linkage-specific ubiquitylation patterns as highly sensitive markers for neurodegenerative disease

Award Number: R44AG054313
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2021

Group Awards By:

View Award Description

Linkage-specific ubiquitylation patterns as highly sensitive markers for neurodegenerative disease - While sensitive imaging tools to detect ß amyloid and tau proteins and other biomarkers for established Alzheimer’s disease (AD) and other neurodegenerative diseases are available, similar tools for detecting pre- symptomatic, etiologic biomarkers of these diseases are not. Among the earliest steps in AD is a failure of the ubiquitin proteasome pathway to respond to misfolded proteins by causing their degradation, thereby promoting aggregation. This early pathological event is marked in part by changes in protein ubiquitylation patterns in neuronal cells. “Ubiquitylation patterns” encompasses multiple ubiquitin chains and lysine positions, and this information is far more complex than a simple ubiquitylation event. In addition, ubiquitylation patterns in neuronal cells of AD patients change as the disease progresses. No non-invasive blood test for pre-symptoms or etiology of Alzheimer ’s disease has been approved by the FDA. In addition to diagnosis, the ability to identify molecular signatures of AD could help stratify the patient population, and changes in ubiquitylation patterns could be used to monitor the clinical efficacy of drugs that target the ubiquitin proteasome system. The aim of this project is to capture the initial step in neurodegenerative disease establishment as well as stages in disease progression by identifying appropriate ubiquitylation pattern signatures that can be detected routinely in a diagnostic assay. Toward this end, in Phase I, LifeSensors developed a highly sensitive method to isolate poly-ubiquitylated proteins based on Ub chain selectivity using TUBES – an affinity matrix that can bind selectively to various distinct poly-Ub chains -- in concert with mass spectrometry (MS) to identify molecular signatures based on ubiquitylation. Conditions were simulated in neuronal cells that mimic neurodegeneration, and marker proteins were identified; in addition, methods were developed to identify low levels of ubiquitylated proteins and observe changes in ubiquitylation patterns from cerebrospinal fluid (CSF) of normal and AD patients. In Phase II, it is proposed to extend these studies to examine CSF and serum ubiquitylated protein molecular signatures from approximately 100 normal and AD patients. LifeSensors will collaborate with Drs. Nicholas Seyfried and Allan Levey of the Alzheimer’s Disease Research Center, leaders in AD proteomics, to translate the tools developed in Phase I to monitor ubiquitylation pattern changes in CSF of normal controls and AD patients and to establish biomarker panels that distinguish controls from AD patients at various disease stages, validating the markers using existing databases and predictive studies. Success in Phase II will lead to the discovery of novel ubiquitylation signatures for various stages of AD. LifeSensors will commercialize stable isotope labeled versions of these proteins to quantify the markers by mass spec in the serum and/or CSF. These simple tests will stratify patient populations to monitor efficacy in clinical trials and guide the choice and dosage of drug to treat AD.


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: 2022 ( Subtotal = $0 )
2022	2019	LIFESENSORS INC	271 GREAT VALLEY PKWY	MALVERN	PA	19355	CHESTER	USA	Aging Research	000	3	1/26/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $779,745 )
2019	2019	LIFESENSORS, INC.	271 GREAT VALLEY PKWY	MALVERN	PA	19355	CHESTER	USA	Aging Research	000	3	5/20/2019	NON-COMPETING CONTINUATION	$779,745
														Subtotal = $779,745

Issue Date FY: 2018 ( Subtotal = $718,511 )
2018	2018	LIFESENSORS, INC.	271 GREAT VALLEY PKWY	MALVERN	PA	19355	CHESTER	USA	Aging Research	000	2	9/21/2018	COMPETING CONTINUATION	$718,511
														Subtotal = $718,511

Grand Total All Awards = $1,498,256

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Linkage-specific ubiquitylation patterns as highly sensitive markers for neurodegenerative disease

Award Number: R44AG054313

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2021

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer