Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Biochemical and molecular heterogeneity of human TDP-43 proteinopathies in age-related dementias

Award Number: R01AG075276
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

Group Awards By:

View Award Description

Biochemical and molecular heterogeneity of human TDP-43 proteinopathies in age-related dementias - The brain is presence of phosphorylated deposits of the neuropathological hallmark of transactive response DNA-binding protein 43 (TDP-43) in the frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). Moreover, in retrospective studies, TDP-43 proteinopathy was shown to be associated with substantial cognitive impairment that mimicked the Alzheimer's disease (AD) clinical syndrome. The co- existence of TDP-43 pathology in brains with neuropathological change of AD (ADNC) has been reported in 30-70% of AD cases, predominantly affecting predominant Recent subtype limbic and associated areas in a pattern called limbic- age-related TDP-43 encephalopathy neuropathological change (LATE-NC). studies have shown that LATE-NC is also found in individuals without ADNC, postulating a new ofTDP-43 proteinopathy designated as LATE. LATE is one of the most prevalent subsets of TDP-43 proteinopathies observed in ~30-50% of people who die beyond 85 years of age. When comparing LATE-NC with FTLD-TDP cases, recent studies have shown that besides distinct clinical manifestations, there are also differences in epidemiological, genetic, and neuroimaging features. From a neuropathological standpoint, LATE-NC and FTLD-TDP individuals share some features of TDP-43 pathology. Since phosphorylated TDP-43 was identified as the major component of ubiquitin-positive inclusions in FTLD-TDP, five distinct FTLD-TDP histopathological distribution and morphological features of TDP-43 aggregates (type between clinical symptoms, genetic forms of FTLD-TDP, and TDP-43 neuropathological subtypes have been established based on characteristic A to E) features . The association in FTLD-TDP brains have been extensively reported. Interestingly, although TDP-43 pathology in some LATE-NC cases resembles FTLD-TDP type A, a distinctive neuropathological feature related to TDP-43 proteinopathy in elderly individuals is type “Alpha” (similar to type A) or type “Beta” (co-mingling with tau tangle structures) pattern of TDP-43 immunoreactivity in the amygdala. The molecular mechanism(s) underlying the heterogeneity of the TDP-43 proteinopathies is still unknown. Such heterogeneity supports a “strain hypothesis” wherein unique pathogenic TDP-43 species (a.k.a. strains) with different conformations may play a role in such diversity. Our objective is to isolate pathogenic TDP-43 species present in FTLD-TDP and LATE-NC brains and characterize their biochemical properties and biological activities in vitro and in vivo (Aim 1). We will then generate in vitro brain-derived TDP-43 strains that recapitulate the characteristic features of their human counterparts (Aim 2). Finally, we will determine whether there are differential pathophysiological signaling pathways associated with neuropathological changes of TDP-43 pathology in the brain by performing spatial profiles between distinct TDP-43 proteinopathies transcriptomic analysis and comparing the expression (Aim 3 ).


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: 2026 ( Subtotal = $596,378 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	5	4/9/2026	NON-COMPETING CONTINUATION	$596,378
														Subtotal = $596,378

Issue Date FY: 2025 ( Subtotal = $510,842 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	4	4/1/2025	NON-COMPETING CONTINUATION	$469,142
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	001	4	6/10/2025	NON-COMPETING CONTINUATION	$41,700
														Subtotal = $510,842

Issue Date FY: 2024 ( Subtotal = $629,616 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	3	4/17/2024	NON-COMPETING CONTINUATION	$629,616
														Subtotal = $629,616

Issue Date FY: 2023 ( Subtotal = $693,011 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	2	5/5/2023	NON-COMPETING CONTINUATION	$693,011
														Subtotal = $693,011

Issue Date FY: 2022 ( Subtotal = $590,839 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	1	7/8/2022	NEW	$590,839
														Subtotal = $590,839

Grand Total All Awards = $3,020,686

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Biochemical and molecular heterogeneity of human TDP-43 proteinopathies in age-related dementias

Award Number: R01AG075276

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer