Funding Opportunity Number: PAR-24-203
Deadlines
Letter of Intent: September 4, 2024
Submission: October 4, 2024
Objectives
The goal of this initiative is to solicit applications that propose studies in animal, cell culture, and/or human tissue models to elucidate the mechanisms by which COVID-19 interacts with and/or modulates ADRD-relevant mechanisms and outcomes. Either the model itself or the experimental readouts must incorporate ADRD risk factors, causes, pathologies, or relevant comorbidities. To this end, proposals should ultimately be centered around one or more of the following:
- Mechanistic studies that address how COVID-19 impacts CNS pathology and cognitive decline when ADRD pathology is already present (for example, in a model of ADRD).
- Mechanistic studies that address how COVID-19 accelerates ADRD pathology in a prodromal model (early phase, pre-symptomatic).
- Mechanistic studies that address how COVID-19 predisposes for ADRD and/or interacts with relevant comorbid conditions and ADRD risk factors (cellular mechanisms that could increase the risk for ADRD development, with experimental readouts that are directly relevant to dementia).
- Mechanistic studies that address how pre-existing ADRD enhances the risk of more severe post-COVID-19 neurological outcomes.
For this initiative, examples of mechanisms of interest include (but are not limited to):
- Direct or indirect effects of COVID-19 on brain microvascular endothelial cell viability and/or barrier function which could exacerbate or trigger VCID.
- Potential mechanisms of SARS-CoV-2 interactions at the BBB and the subsequent effects on perivascular spaces and VCID phenotypes.
- Mechanisms of COVID-19-associated peripheral to CNS crosstalk that result in neurological sequelae and have the potential to modulate ADRD-relevant pathology.
- COVID-19-induced chronic neuroinflammation and how this relates to specific mechanisms of neurodegeneration such as synaptic pruning by microglia, prolonged cerebrovascular dysfunction, and/or aberrant neuroimmune activation states.
- SARS-CoV-2-induced hypothalamic-pituitary-adrenal (HPA) axis dysfunction as it relates to immune dysregulation (e.g., T cell exhaustion), neuroinflammation (e.g., IL-6 and other cytokine expression), and sickness behaviors such as chronic fatigue.
- Research on COVID-19-induced CNS-specific autoimmunity and/or autoantibodies that may result in damage to the cerebrovasculature and other CNS cell types.
- How pathological cellular events in the white matter, such as aberrant glial activation, demyelination, and/or impaired neurogenesis and neurotrophic support, are induced and/or potentiated by COVID-19 to promote or exacerbate ADRD-relevant pathology and phenotypes.
- Mechanisms by which COVID-19 modulates the initial seeding, accelerates the propagation, and/or affects the degradation and clearance of ADRD-relevant pathological protein aggregates.
- Studies focused on potential mechanisms of brain mitochondrial dysfunction and reactive oxygen species (ROS) production in the context of COVID-19 and ADRD.
- Research focused on the interplay between COVID-19 and other latent CNS infections that exhibit associations with neurodegeneration and/or ADRD (i.e., Epstein Barr Virus, Herpes Simplex Virus, Human Immunodeficiency Virus, etc.).
- The potential impact of pre-existing ADRD or ADRD-relevant comorbidities on Neuro-PASC mechanisms and phenotypes.
- Research to better understand the interactions between COVID-19 and ADRD in the context of new emerging SARS-CoV-2 variants and repeated rounds of infection.
- While some forms of human subjects research are out of scope (see below), the use of de-identified human samples and clinical data (such as from one of the RECOVER repositories or other relevant sources) is allowed for this initiative, as long as this is incorporated with a mechanistic component. Since the NINDS is committed to reducing the disproportionate burden of neurological disease borne by underserved groups of society (including racial and ethnic minority, rural, and socioeconomically disadvantaged populations), the inclusion of de-identified human samples from such populations is strongly encouraged.
For more information, please see the opportunity website.