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

Defining modifiers and mechanisms of RAN translation

Award Number: R01AG064690
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2028

Group Awards By:

View Award Description

Defining modifiers and mechanisms of RAN translation - Project Summary/Abstract Defects in protein translation are central to multiple neurodegenerative diseases, including Alzheimer’s disease and related dementias (e.g., frontotemporal lobar dementia). An unconventional form of translation has been shown to play a role in several neurodegenerative diseases associated with nucleotide repeat diseases. In these diseases, expanded nucleotide repeats get translated in an AUG-independent manner to produce aberrant peptides that may contribute to neurodegeneration. The mechanism of this unusual form of translation, called RAN translation, has remained poorly understood. The Gitler and Puglisi laboratories have joined forces to combine biophysics and genetics approaches to elucidate the mechanism of RAN translation. We developed new single-molecule methodologies to study translation dynamics in humans and combined these with biochemical and in vivo approaches to reveal a global mechanism for RAN translation and identified potent modifiers of RAN translation, at least one of which could mitigate degeneration in several frontotemporal dementia and amyotrophic lateral sclerosis (ALS) disease models. We propose new studies to gain even deeper understanding of RAN translation. We will also expand and extend our efforts to investigate a new facet of frontotemporal dementia (FTD) pathology that we recently discovered – altered processing of the 3’ end of certain mRNAs, which are targets of the FTD and ALS disease protein TDP-43. These altered 3’ ends of the mRNAs has profound effects on the translation of the mRNAs and we have evidence that at least one of them is directly linked to FTD. Our results will build on the foundation of the prior funding period and establish a coherent dynamic mechanism of RAN translation and its regulation from initiation through protein production. We will also illuminate a new facet of TDP-43 pathology in FTD and ALS and how this impacts protein translation. More broadly, our results will provide a mechanistic foundation for understanding the interplay of translation dynamics and fidelity and protein quality control in aging and neurodegenerative diseases, including dementia.


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 = $746,766 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	4	4/9/2026	NON-COMPETING CONTINUATION	$746,766
														Subtotal = $746,766

Issue Date FY: 2025 ( Subtotal = $744,302 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	3	4/9/2025	NON-COMPETING CONTINUATION	$683,542
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	001	3	6/13/2025	NON-COMPETING CONTINUATION	$60,760
														Subtotal = $744,302

Issue Date FY: 2024 ( Subtotal = $771,846 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	2	5/14/2024	COMPETING CONTINUATION	$771,846
														Subtotal = $771,846

Grand Total All Awards = $2,262,914

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Defining modifiers and mechanisms of RAN translation

Award Number: R01AG064690

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer