Wednesday, October 9, 2024
10/9/2024
Project Summary/Abstract Lung damage is the most common extracranial pathology in survivors of traumatic brain injury (TBI). Recent findings from multiple laboratories have collectively suggested that the protein tau, known to be released after TBI into circulation, can (1) damage pulmonary vascular permeability, (2) be internalized by endothelial cells in a heparan-sulfate proteoglycan (HSPG) dependent manner, and (3) can impair nitric oxide production, critical for vasodilatory regulation. While there is strong correlation between tau accumulation in the brain and dementia, there is a critical gap in understanding the acute effects of tau on vascular endothelium in trauma. Our lab has preliminary evidence that a soluble pathogenic tau peptide can disrupt endothelial Ca2+ dynamics, cause vasoconstriction, impair endothelial-dependent vasodilation, and disrupt local cerebral blood flow within minutes of exposure. Others have demonstrated that polyanions such as heparin can inhibit endothelial cell uptake of tau from the surrounding environment. Due to concerns of coagulopathy in trauma and heparin’s potent anticoagulative properties, I propose investigating the efficacy of suramin, an alternative polyanion and malaria drug, in protecting the endothelium from tau after TBI. My central hypothesis is that blast injury results in systemic tau release into the circulation that is acutely internalized by endothelial cells via HSPG binding, and prevention of this internalization using suramin will minimize endothelial damage in the brain and lung.To test this hypothesis, I will first determine the extent to which tau alters endothelial calcium signals and vasodilation. This will be accomplished through myography of ex vivo pulmonary and cortical arteries treated with soluble T peptide, with and without pretreatment with heparin. I will additionally assess the vasodilatory and calcium responses to tau in the intact brain and lung using in vivo multiphoton imaging. Second, I will evaluate the use of polyanions to prevent tau internalization, endotheliopathy, and organ failure in a preclinical model of TBI. I will use a blast model of mouse TBI and determine whether acute treatment with heparin or suramin can ameliorate trauma- induced vasodysfunction using myography of isolated arteries as well as histology of both brain and lung tissues. As secondary outcomes, I will evaluate suramin’s efficacy in preventing pulmonary barrier function degradation and edema, as well as improving recovery of spatial memory after blast TBI. Ultimately, this proposal aims to improve understanding of extracellular tau on systemic endotheliopathy and propose a novel, rapidly available therapeutic for TBI and its associated extracranial pathology. This proposal outlines a comprehensive training experience in which I will gain and utilize new expertise in both ex vivo and in vivo assessments of vasodilation and calcium activity, as well as in preclinical trial design and evaluation of pulmonary and cognitive function. I will work closely with a multidisciplinary mentoring committee to further both my investigative abilities and career development.
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