Related Announcements

PAR-22-093, Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)

Issued by

National Institute on Aging (NIA)

Purpose

Glycosylation is a post-translational modification in which a sugar (or carbohydrate) is attached to a hydroxyl or other functional group of a macro molecule (such as DNA, lipids and proteins). Most glycosylated proteins are glycosylated in the rough endoplasmic reticulum (ER) or Golgi by glycosyltransferases. Likewise, specific serine or threonine hydroxyl moieties on nuclear and cytoplasmic proteins can be modified by N-acetylglucosamine (O-GlcNAc) transferase (OGT), which adds a single sugar N-acetylglucosamine. Glycosylation is known to affect various cellular and physiological functions including regulation of enzymatic activities, cell differentiation and morphogenesis.

Currently, approaches for both basic and clinical biology of Alzheimer's disease (AD) are largely focused on disease-related changes at the genomic, epigenetic, transcriptomic, and proteomic level(s). However, there are many different aspects of biology and cellular biochemistry that cannot be explained by these types of systems approaches. Glycosylation and complex carbohydrates have been reported to play many critical roles in the early pathogenesis and progression of AD, but the potential of these molecules to serve as biomarkers and targets of disease intervention remains largely unexplored.

Recent studies have also suggested that the deficiency of a sulfotransferase for sialic acid-modified glycan could mitigate AD pathology and binding of Aß to various AD-risk glycoproteins such as TREM2, which are likely regulated by the change of glycans on these molecules as well. Small molecules that are known to block the interactions of Aß and glycans have been shown to increase survival advantage of neurons in mouse models of AD. Together, these findings indicate the potential of glycomic aberrations as potential biomarkers and targets of disease prevention. Despite the importance of glycosylation and altered glycan structures in AD, the aberrant molecular and biochemical function of these glycosylated molecules to serve as disease modifiers remain largely elusive.

Traditionally, it has been very difficult to study and monitor the alteration of glycosylation and glycans in relation to aging and early initiation of AD. However, several recently developed technologies now allow one to systematically monitor the change of protein glycosylation and glycans in various biological fluids from a large number of individuals. Therefore, the goal of this Notice of Special Interest (NOSI) is to invite research projects using state-of-the-art methods of protein carbohydrate analyses to understand the potential impact of glycosylation on the etiology of AD and biomarker discovery.

Areas of high program relevance include, but are not limited to, the following:

• Precise biochemical and molecular mechanisms of altered glycan structures underlying the propagation of pathological protein assemblies in AD, including the role of glial cells and other non-neuronal cell types.
• Molecular, cellular, and physiological studies of glycobiology to define the functional sequences of genetic risk factors for AD.
• Understanding the roles of extracellular matrix and proteoglycans in modulating synaptic degeneration and accumulation of AD-related pathologies.
• Impact of microenvironment, such as plaque accumulation, on altered glycans and their roles as potential biomarkers and disease modifiers.
• Consequences of aberrant glycosylation on the unfolded protein response and protein homeostasis.
• Understanding the roles of chronic inflammation and immune surveillance in response to altered glycans during the course of AD.

Application and Submission Information

This notice applies to due dates on or after March 11, 2022 and subsequent receipt dates through November 13, 2024. 

Submit applications for this initiative using the following funding opportunity announcement (FOA) or any reissue of the announcement through the expiration date of this notice.

• PAR-22-093, Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-AG-21-042” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Please direct all inquiries to:

Austin Yang, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350 
Email: yangj13@mail.nih.gov