A recent NIH-sponsored Hydrocephalus Symposium highlighted the critical unmet need to develop effective non-surgical hydrocephalus therapies based on improved understanding of the choroid plexus epithelium (CPe) and its mechanisms of cerebrospinal fluid (CSF) secretion. These knowledge gaps perpetuate current reliance CSF shunting surgeries with high morbidity and failure rates. The scientific premise of this proposal is based on our recently published (Nature Medicine, 2017) and unpublished data suggesting the CPe?s immuno- secretory plasticity plays an essential role in the pathogenesis of acute post-hemorrhagic hydrocephalus (PHH) via a toll-like receptor-4 (TLR4)-dependent increase in CSF secretion regulated by the NF-?B-regulated SPAK kinase. However, several fundamental questions require elucidation: (i) How does intraventricular hemorrhage (IVH) cause CPe inflammation? (ii) Which CPe ion transporters are required for the CSF hypersecretory response? (iii) Does this mechanism contribute to the pathogenesis of post-infectious hydrocephalus (PIH)? (iv) Can drug inhibition of TLR4, SPAK, or other CPe targets post-IVH or infection prevent or attenuate hydrocephalus? These questions frame our central hypothesis that CSF-borne damage- and pathogen- associated molecular patterns (DAMPs and PAMPs) associated with IVH (methemoglobin) and bacterial meningitis (lipopolysaccharide [LPS]), stimulate TLR4/MyD88 signaling to cause CPe inflammation, and the associated CSF hypersecretory response requires a functional ensemble of SPAK-regulated CPe ion transport proteins. This hypothesis will be tested in 3 specific aims: (1) elucidate the TLR4-dependent CPe inflammatory mechanism(s) triggered by IVH; (2) identify the TLR4-dependent CPe ion transport effectors that mediate IVH- induced CSF hypersecretion; and (3) characterize the effects of bacterial PAMPs central to PIH on CPe immuno-secretory function. To do this, we will use wild type and TLR4 knockout rats in a validated model of PHH, and our novel LPS-induced model of PIH, and employ direct in vivo real-time monitoring of CSF secretion; non-invasive MR imaging of ventricular volume in live animals; quantitative CPe phospho- proteomics to interrogate signaling networks; and the intracerebroventricular delivery of drugs and antisense oligonucleotides to modulate CPe targets. Our study's overall objective is to identify specific CPe inflammatory and/or ion transport proteins that can be pharmacologically leveraged to prevent hydrocephalus, thereby bringing us nearer to our long-term goal of eliminating surgical shunt dependence. Our proposal is innovative because it challenges the status quo conceptual, methodological, and therapeutic approaches to hydrocephalus. If successful, this work could catalyze a change in our view of hydrocephalus from a neurosurgical ?brain plumbing? disorder to a drug-preventable neuro-inflammatory condition. In advancing our basic understanding of CPe immuno-secretory function, this work may also inform development of novel therapeutic strategies for other conditions associated with neuroinflammation or disordered CSF dynamics.
PUBLIC HEALTH RELEVANCE: Hydrocephalus is a major cause of morbidity and mortality, affecting 1 in 1,000 live births, and costing the U.S health care system greater than $2 billion annually. Over the last few decades, there has been little progress in the prevention or treatment of hydrocephalus, and current therapy relies largely on suboptimal surgical cerebrospinal fluid (CSF) shunting procedures with high rates of failure and morbidity. The development of targeted pharmacological therapies for hydrocephalus based on an improved understanding of the molecular pathophysiology of the disease would benefit millions of patients worldwide.
