Team Hydro’s philosophy in funding research grants is simple:
- We support research with the potential to move science towards a cure for Hydrocephalus, rather than just small variations on the clinical status quo. This includes projects that seek to uncover the basic biology underlying this disease, to determine and halt causative factors, and to generate innovative new approaches to therapy.
- We support promising researchers with potential for long-term impact on the field. The lifeblood of academic research in the U.S. is, generally speaking, large federal grants issued via the NIH, the DoD, and other public research agencies. We have no intention to replace these agencies! However, it is currently impossible for new researchers (especially those interested in under-funded conditions like Hydrocephalus) to qualify for lab-sustaining grants from these departments without preliminary data. By the same token, commercial R&D typically enters the foray only after preliminary data developed via private and public investment. At Team Hydro, we seek to provide hydrocephalus researchers with seed funding that will enable them to assemble the critical mass of data necessary to bridge the gap towards the major public grants (and/or commercial development). In doing so, we hope to help their labs to become self-sustaining entities for research, discovery, and the training of new talent that will continue in the field for many years to come.
To this end, Team Hydro has funded over $800,000 of research to date and supported a range of research grants in the U.S., Australia, and Canada. Importantly, all our grantees are selected as a part of rigorous peer review process in conjunction with expert panels at the Hydrocephalus Association. Finally, as we proudly state elsewhere, all Team Hydro fundraising dollars are applied directly towards grant funding — not overhead costs.
We at Team Hydro have been extremely pleased with the results of this investment model so far. In fact, we have already seen more than $5 Million in follow-up grants to Team Hydro labs through the NIH and Department of Defense. See below for descriptions of the projects we’ve funded to date.
Current and Former Projects Sponsored by Team Hydro
Reprogramming scar tissue into healthy ependymal cells — Taraviras Lab, University of Patras, Greece
Human hydrocephalus is characterized by an abnormal circulation/accumulation of cerebrospinal fluid in the brain ventricles. Loss and/or dysfunction of ependymal cells has been linked to hydrocephalus formation in mice and humans. Current treatment of hydrocephalus only partially relieves the symptoms leaving the disease basically untreated. Recent findings identify GemC1/Lynkeas and McIdas, as central regulators of the ependymal cell fate commitment and differentiation, while mutations in GemC1/Lynkeas and McIdas have been associated with hydrocephalus in humans. The goal of this project is to provide evidence for novel directions on hydrocephalus treatment. The researchers will assess the ability of GemC1/Lynkeas and McIdas to induce direct cellular reprogramming towards the ependymal lineage, of cells lining the wall of hydrocephalic mouse models. Towards this direction a genetic mouse model of hydrocephalus established in our laboratory and a mouse model of intracranial hemorrhage will be used. Grant value: $50k
Gene expression in the tissue surrounding the shunt catheter — Harris Lab, Wayne State University
Current understanding of the cellular response contributing to the failure of cerebral spinal fluid (CSF) shunts has been limited, to date, with the evaluation of cells and tissue around the implant. Yet there is a critical knowledge gap in gene expression profiles in this tissue. When paired with cellular analysis, gene expression can lead to understanding the activity of the cells obstructing catheters at the time of shunt failure. This first-time study, which pulls strengths from the recent world-renowned Barres et al. study on astrocyte activation, represents a robust investigation of the changes in gene expression levels specific to astrocyte immune response following CSF shunt implantation. By shedding light on the mystery of astrocyte phenotype expression on shunt surfaces, root causes for shunt failure can be achieved. This Innovator Award will drive urgent investigation into manipulation of astrocyte activity using shunt modification or drug release. Grant value: $25k.
Iron-mediated ventricular injury in posthemorrhagic hydrocephalus — Strahle Lab, Washington University
Previously, this group showed that iron play a key role in the development of hydrocephalus and neuronal cell death after intraventricular hemorrhage. It is not known, however, how iron enters into ependymal choroid plexus cells in the brain to cause this damage. This project will determine the mechanism of iron entry into the ependymal and choroid plexus cells, which will allow for the development of directed treatments to inhibit cellular entry of iron, preventing neuronal damage and hydrocephalus. Grant value: $50k. (Note: This investment resulted in a $2.4M dollar follow-up grant form the NIH! See here for an interview with Dr. Strahle!)
Preclinical Testing of TRPV4 Antagonists for the Treatment of Hydrocephalus– Blazer-Yost Lab, Indiana University – Purdue University Indianapolis
Our preliminary data indicate that TRPV4 antagonists ameliorate hydrocephalus in a rat model of Meckel Gruber Syndrome. The goals of the proposal are to: 1) determine if the efficacy is a class action of TRPV4 antagonists; 2) determine if TRPV4 antagonists are effective in another model of hydrocephalus representing a different species and different genetic mutation and; 3) use a continuous choroid plexus cell line to examine the effect of TPRV4 agonists and antagonists on transepithelial ion flux. Drug treatment will be followed with state-of-the-art rodent MRI for quantification of ventricular volumes. The cell line will be studied using well characterized electrophysiological techniques. If successful, these studies will form the framework for future pharmacokinetic and pharmacodynamic testing of TRPV4 antagonists, and structural/functional studies linking changes in brain metabolism with behavioral changes. The proposed studies will make a substantial contribution to progression toward developing the first drug treatment for hydrocephalus. Grant value: $50k.
Goal: Prove the efficacy of a compound to ameliorate ventriculomegaly in multiple mouse models. (Note: This grant resulted in a $1.3 million follow-up grant from the DOD. See here for a Q&A with Dr. Blazer-Yost!)
Impact of germinal matrix hemorrhage on CSF reabsorption through the glymphatic system — Yan Ding, Loma Linda University
Working at the John H. Zhang’s laboratory at Loma Linda, Dr. Yan Ding is doing pioneering work investigating the role(s) of the brain glymphatic and lymphatic systems in CSF absorption and the development of PHH. These systems, of great interest over the last few years but under-explored to date, may hold therapeutic potential in PHH and other forms of hydrocephalus. Grant value: $50k. (Note: Yan Ding and John Zhang from Loma Linda have received a $1.7M grant from the NIH to study hydrocephalus. See here for an interview with Dr. Ding!)
Pharmacological Prevention of PHH of prematurity — David Limbrick, Washington University in St. Louis
Ventricular zone (VZ) disruption is a fundamental step in the pathophysiology of post-hemorrhagic hydrocephalus (PHH) in preterm infants. This group has reported alterations in VZ cell junction biology underlying VZ disruption in PHH; specifically, N-cadherin-based adherens junctions are compromised in PHH. Linked to this phenomena are a characteristic neuroinflammatory response, reactive astrocytosis, and resulting periventricular white matter pathology. We now have compelling preliminary data implicating the sheddase A Disintegrin and Metalloproteinase 10 (ADAM10)-mediated cleavage of N-cadherin in VZ disruption. In the current project, this group will test the Central Hypotheses that: 1) ADAM10-mediated cleavage of N-cadherin is a fundamental trigger for VZ disruption and the pathogenesis of PHH; and 2) pharmacological inhibition of ADAM10 will prevent the development and pathophysiology of PHH. This highly innovative proposal will provide the first steps toward defining primary molecular mechanisms that lead to PHH. Grant value: $300k.
Response of the Choroid Plexus to Preterm Hemorrhage — Maria Lehtinen, Boston Children’s Hospital (Partial sponsorship via Team Hydro)
Hydrocephalus refers to a constellation of symptoms in conjunction with enlarged cerebral ventricles and/or elevated intracranial pressures, and a common variant of hydrocephalus occurs in the days and weeks following pediatric intraventricular hemorrhage. Because choroid plexus (ChP) is directly exposed to intraventricular blood products and plays a substantial role in cerebral fluid formation and in coordination of normal brain development, its role in post-hemorrhagic hydrocephalus (PHH) warrants more detailed study. This proposal aims to dissect ChP dysfunction in PHH by evaluating cell-type specific changes in gene expression, protein secretion, and fluid pressures primarily in fetal and juvenile rodents, but also with direct comparisons to cerebrospinal fluid (CSF) samples from human pediatric PHH at the Boston Children’s Hospital. Stemming from the lack of therapeutic options for PHH, the experimental designs will also evaluate and lay the groundwork to identify new therapies for ChP dysfunction in pediatric PHH. Grant value: $25k.
Drug Delivery for Posthemorrhagic Hydrocephalus* — Yun Yung, Scintillon Institution (Partial sponsorship via Team Hydro)
The field of hydrocephalus research has made great strides in understanding the etiologies and downstream sequelae of PHH. Numerous genes and blood-derived factors have been identified in preclinical animal models or clinical studies. A major bottleneck for patients now is identifying and optimizing drug delivery and compounds for non-surgical PHH treatment. Promising approaches include opening blood brain barriers (BBB) using physiochemical methods, as well as permeant, target factor-specific nanoantibodies, which are highly novel and innovative. This group will study these novel approaches for PHH treatment using established fetal and neonatal mouse models induced by blood or lysophosphatidic acid (LPA). This proposal’s goals are to understand how LPA signaling affects brain barriers and erythrocytes to improve drug access into PHH brains. Positive results here could be broadly applicable to various forms of hydrocephalus caused by blood or infection and lead to subsequent NIH applications for basic and clinical studies. Grant value: $25k.
A Molecular Shunt for Curing Hydrocephalus– Linninger Lab, University of Illinois
Hydrocephalus has multiple etiologies with a common symptom of water accumulation in the ventricles. The current treatment standard of fluid shunting via a ventricular catheter has remained largely unchanged over the past 50 years. Because water accumulation and fluid exchange within the brain are poorly understood, there is no cure for hydrocephalus. The astrocyte transmembrane protein, aquaporin-4, has been identified as a critical water transport channel. This project seeks to quantify amount and speed of water flux via AQP4 channels. We will use a novel microfluidic platform especially designed to mimic the in vivo morphology of astrocyte networks to study intracellular water transport. The new insights and data will create the foundation for managing and restoring cerebral water transport by pharmacological intervention. The envisioned pharmacological therapy would eliminate pathological water accumulation via molecular shunting, apt to cure hydrocephalus rather than merely treating its symptoms. Grant value: $50k.
Goal: Develop an in vitro system that measures fluid dynamics and to test drugs that have the potential to improve fluid removal in hydrocephalus.
Therapeutic Modulation of Post-Hemorrhagic Hydrocephalus– McAllister Lab, Wash U.
Few attempts have been made to pharmacologically modulate the pathophysiology of hydrocephalus. However, we recently demonstrated that intraventricular infusions of “Decorin” significantly reduce neuroinflammation and prevent ventriculomegaly if given at the onset of hydrocephalus. Our collaborators have also developed a chemokine antibody that protects against demyelination4. These promising results require further study in a clinically relevant model of hydrocephalus. Neuroinflammatory processes are hallmarks of hydrocephalus, and likely contribute to increases in brain stiffness observed clinically. Brain stiffness can be measured non-invasively with novel magnetic resonance elastography (MRE); this new technique will be used, in combination with other assessments of white matter integrity, cerebrospinal fluid (CSF) biomarkers, intracranial pressure (ICP), and cytopathology to identify specific drug targets and evaluate the effects of drug treatments. Our studies focus on post-hemorrhagic hydrocephalus (PHH) because of its prevalence. Our findings will lead to further development of treatments that could dramatically improve patient outcome. Grant value: $50k.
Goal: Develop a higher model of post-hemorrhage hydrocephalus and determine the efficacy of one drug in stopping disease progression.
Analysis of the role of NFIX in the development of hydrocephalus– Piper Lab, University of Queensland
Our preliminary data have revealed a key role for the transcription factor NFIX in regulating the normal development of neural stem cells within the subventricular zone and of the ependymal cell layer of the lateral ventricles . Moreover, rodents  and humans  with reduced NFIX expression exhibit abnormal ventricular enlargement, implicating NFIX in the development of hydrocephalus. However, the processes underpinning this remain to be identified. Here we propose to use a suite of innovative techniques, coupled with an Nfix knockout mouse strain, to assess the cellular and molecular mechanisms by which NFIX mediates neural stem cell differentiation and subsequent ependymal cell development. Collectively this study will characterize the role of NFIX in the development of the ventricular system of the brain, and will provide crucial molecular insights into the formation of hydrocephalus, research that will provide the foundation towards developing strategies aimed at ameliorating this debilitating disorder. Grant value: $25k.
Augurin as a novel choroid plexus-derived peptide hormone that regulates CSF formation by controlling epithelial cell homeostasis– Sonia Podvin and Andrew Baird, UCSD
The study hypothesized that the peptide hormone, augurin, is produced and secreted by the choroid plexus epithelium, is a ligand for an unknown receptor and has a critical function in CSF fluid homeostatsis. If proven, researchers predict that augurin can be manipulated pharmacologically to treat hydrocephalus. Grant value: $110k. See here for a Q&A with Dr. Podvin!