Notice Number: NOT-AG-24-032
First Available Due Date: March 11, 2025
Expires: November 17, 2027
Research Objectives
This NOSI invites applications that aim to establish the role and underlying mechanisms by which brain aging impacts the development and progression of AD. A comprehensive and integrative characterization of brain aging, including its crosstalk with peripheral systems and factors, will help to define the mechanisms underlying the shift from normal aging to pathological processes in the etiology of AD. To gain a deeper understanding of the complex biology and physiology of healthy and pathologic brain aging, cross-disciplinary, systems-based approaches using newly developed tools and technology to integrate findings on AD with research on the basic biology and neurobiology of aging are encouraged. Animal and human studies are appropriate for this NOSI.
Areas of research interest and opportunity include, but are not limited to, the following:
- Characterize in a systematic, integrative way how aging processes (e.g., hallmarks of aging, genomic instability, epigenetic changes, senescence, macromolecular damage, mitochondrial/energy dysfunction, proteostasis dysfunction, loss of calcium homeostasis, loss of neural stem cells, inflammation/immunity, and alterations in stress responses) impact the development and/or progression of AD pathophysiology in brain.
- Define genetic, molecular, and metabolic neural profiles in conjunction with behavioral profiles that distinguish normal brain aging from pathological aging.
- Employ a lifespan approach to study the genetic, epigenomic, proteomic, lipidomic, metabolic, and other molecular changes during vulnerable periods/physiological transition states to understand the mechanisms behind protective and risk factors.
- Characterize the role of the proteostasis network, intracellular organelle interaction, or cell-cell communication in brain protection and degeneration (e.g., due to proteotoxicity) in aging and AD.
- Characterize the impact of age-related changes in glial cells (e.g., astrocytes, microglia, oligodendrocytes) and other non-neuronal cells in AD pathophysiology.
- Identify neural cell populations, brain regions, neural circuits, and/or large-scale networks (connectome) that are vulnerable during brain aging and contribute to AD.
- Define the age-related aberrant or compensatory neural activities in epileptogenic, sensory, motor, emotional, cognitive, or sleep systems that contribute to AD.
- Characterize the molecular, cellular, synaptic, and neural circuitry mechanisms underlying brain plasticity (e.g. neurogenesis or adaptive cell stress response pathways) in aging and AD.
- Elucidate molecular, cellular, and physiological changes in the brain glymphatic and lymphatic transport systems during aging and their contribution to the development of AD.
- Integrate research aimed at understanding the epigenetics, genetics, molecular and cellular networks, neural connectivity, and complex biology of brain resilience and/or cognitive resilience in aging and AD.
- Study the integrative physiology of sleep and whether disruption of sleep and/or circadian clock accelerates brain aging and AD neurodegenerative change.
- Elucidate the short- and long-term consequences of disrupted and optimized sleep on brain aging and AD.
- Elucidate the impact of sex differences on the trajectories of brain aging and AD.
- Develop integrative research to understand how aging in peripheral systems (e.g., immune, endocrine, metabolic, microbiome) interact with the CNS to impact brain aging and the initiation and progression of AD neurodegenerative changes.
- Develop and employ novel animal models, such as rodents, canines, and non-human primates, which can spontaneously develop neuropathological signs of AD at older ages.
- Use human cell reprogramming approaches (e.g., iPSCs) and 3D or organoid culture approaches to study molecular, physiological, and systems cell biology of aging and AD.
- Molecular, cellular, and physiological studies to define the mechanisms of successful super agers that represent resistance or resilience to pathology and memory decline.
- Identification of the upstream/initiation cause of ‘sporadic’ TDP-43 loss of function, mislocalization, and cytoplasmic aggregation during aging. Define the connection between TDP-43 dysfunction, aggregation, and mislocalization.
- Characterize how age-related changes in the cerebrovasculature, neurovascular unit, and blood-brain barrier contribute to the pathophysiology of AD.
- Characterize age-related changes in hormone release, receptors, and signal transduction and the consequent impact on development and/or progression of AD.
For more information, please see the opportunity website.