Heme regulates neurocognition by modulating Tau pathology in sickle cell disease
NINDS - National Institute of Neurological Disorders and Stroke
About This Grant
Project Summary Majority of Individuals with sickle cell disease (SCD) experience neurocognitive complications including cerebrovascular lesions with poor performance in learning and memory functions. Cognitive impairment is a risk factor of dementia. The vascular contributions to cognitive impairment and dementia (VCID) in SCD have not been reported. Hemolysis within the cerebrovascular space representing severe anemia, is a strong predictor of neurocognitive impairment in SCD. Excess circulating free heme, a byproduct of intravascular hemolysis, is implicated for multiorgan complications in SCD. However, the mechanistic approaches interpreting the heme- driven pathogenesis of VCID linking cerebral microvasculature with cognitive impairment in SCD are lacking. In pilot studies, we discovered that heme instigates phosphorylation of microtubular associated protein Tau (pTau) in the cerebrovascular endothelium of transgenic SCD mice. Free heme activates endothelial toll-like receptor 4 (TLR4) and insulin growth factor binding protein 3 (IGFBP3) associated with Tau phosphorylation. Sickle bone marrow chimera mice deficient in TLR4 had reduced pTau associated with impeded IGFBP3 expression in the cerebrovascular endothelium. Moreover, heme induced the intercellular protein transporter, low-density lipoprotein receptor -1 (LRP1) in the microvessel adjacent astrocytes, where pTau was accumulated following heme challenge. Based on these preliminary data, we formulated the overarching hypothesis that heme triggers phosphorylation of endothelial Tau that is accumulated in the astrocytes via LRP1 and promotes neuroaxonal damage and cognitive impairment in SCD. In Aim 1, we will perform magnetic resonance angiography (MRA), diffusion tensor and weighted imaging (DTI/DWI), immunohistopatholgy, cognitive testing (Y-maze and novel object recognition), and bone marrow trasplantation (BMT) to assess the role of Tau in the development of heme-induced cognitive impairment in sickle mice. In Aim 2, we will determine whether TLR4-IGFBP3 signaling stimulates Tau phosphorylation. Aim 3 will determine the role of LRP1 in pTau accumulation and calcium signaling in the astrocytes. Overall, this study aims to determine the role of heme in the pathogenesis of neurovascular damage and cognitive impairment, delineating an innovative VCID pathway in SCD.
Grant Summary
Heme regulates neurocognition by modulating Tau pathology in sickle cell disease is a NINDS - National Institute of Neurological Disorders and Stroke grant providing up to $515K for university, nonprofit, healthcare org. Applications are due 2031-03-31 (open). Check eligibility and apply with FindGrants.
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Eligibility
How to Apply
Up to $515K
2031-03-31
- 1Confirm your organization is eligible for Heme regulates neurocognition by modulating Tau pathology in sickle cell disease from NINDS - National Institute of Neurological Disorders and Stroke, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
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Heme regulates neurocognition by modulating Tau pathology in sickle cell disease: Frequently Asked Questions
Who is eligible for the Heme regulates neurocognition by modulating Tau pathology in sickle cell disease?
Heme regulates neurocognition by modulating Tau pathology in sickle cell disease is offered by NINDS - National Institute of Neurological Disorders and Stroke and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Heme regulates neurocognition by modulating Tau pathology in sickle cell disease provide?
Heme regulates neurocognition by modulating Tau pathology in sickle cell disease provides up to $515K per award from NINDS - National Institute of Neurological Disorders and Stroke. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Heme regulates neurocognition by modulating Tau pathology in sickle cell disease deadline?
Applications for Heme regulates neurocognition by modulating Tau pathology in sickle cell disease are due 2031-03-31 (open). Because deadlines can change, verify the date with the funder, NINDS - National Institute of Neurological Disorders and Stroke, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Heme regulates neurocognition by modulating Tau pathology in sickle cell disease?
To apply for Heme regulates neurocognition by modulating Tau pathology in sickle cell disease, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NINDS - National Institute of Neurological Disorders and Stroke.