Notice Number: NOT-AG-24-033
First Available Due Date: March 11, 2025
Expires: November 17, 2027
Research Objectives
The goal of this NOSI is to stimulate research to define and characterize neural cell populations (e.g., neurons and glia), neural activity and circuits, structural and functional networks, and brain regions that are vulnerable (or resistant) in brain aging and AD as well as the mechanisms underlying such selective vulnerability. Genetic and molecular signatures of different types of neurons and glial cells across the adult lifespan, in AD compared to other dementias of aging as well as in different stages of AD, will implicate cell processes and pathways mediating selective vulnerability in AD. Defining cell types by physiological measures such as electrophysiology and connectivity and manipulating neural activity in circuits and networks will provide a functional index of selective vulnerability. Applicants are encouraged to use new approaches to generate sophisticated data on molecular signatures of brain cells and on structure and function of brain circuits and networks. Understanding the mechanisms underlying selective vulnerability from cells to networks in AD is critical to fully define the disease process and to develop effective therapies.
Areas of research interest and opportunity include, but are not limited to, the following:
- Identification of neural cell populations, brain regions, neural circuits, and/or large-scale networks (connectomes) that contribute to vulnerability in brain aging and AD.
- Study of comprehensive single-cell transcriptomics, epigenetics (e.g. chromatin remodeling, DNA methylation), and/or genomics (e.g. somatic mutations, DNA damage) of neurons and glial cells in different brain regions at different ages and pathological stages of AD.
- Identification of genetic, proteomic, lipidomic, metabolomic, and bioenergetic signatures and drivers of cellular vulnerability and plasticity in brain aging and AD.
- Use of multidisciplinary and multiplexed technological approaches to single-cell ‘omics,’ electrophysiology, and connectivity for comprehensive and integrative studies of selective vulnerability to neuro- and glial-degeneration in aging and AD.
- Identification of mechanisms underlying selective cell sensitivity to beta-amyloid, tau, and other proteinopathies, including cell-to-cell spread of pathogenic proteins.
- Identification of the role of the proteostasis network or intracellular organelle interaction in selective cell and circuitry vulnerability.
- Identification of the role of mitochondrial health, function, and maintenance in selective vulnerability over time.
- Identification of the role of cell-intrinsic versus cell non-autonomous, peripheral organ systems, endocrine, and/or environmental factors in selective vulnerability or adaptive responses to cell or network stressors or neurodegenerative events.
- Characterization of the molecular, metabolic, cellular, synaptic, and neural circuitry mechanisms underlying brain plasticity, including protective and resilience processes, in counteracting vulnerability to neurodegeneration in aging and AD.
- Identification of the role of differential activity and connectivity properties of neuronal populations, circuits, and networks in vulnerability (or resiliency) to aging and AD.
- Define a cryptic exon atlas of TDP-43 dysfunction by investigating cryptic splicing across different cell types. Elucidate broadly expressed and cell-specific cryptic exons.
- Develop systematic approaches to probe the cell type-specific function of splicing alterations and identify RNA targets that contribute to disease progression. Understand the cell type-specific vulnerabilities to TDP-43 pathology.
For more information, please see the opportunity webpage.