Research Award in Cerebrospinal Fluid (CSF) Production, Flow, and Regulation Therapeutics and Diagnostics
Request for Applications
The Hydrocephalus Association in partnership with The Rudi Schulte Research Institute (RSRI) announces a Request for Applications. Rudi Schulte was one of the two founders of a shunt manufacturing company called PS Medical, later acquired by Medtronic. Through his ground-breaking work, the hydrocephalus shunt was developed. Later, in order to further advance research in the treatment of hydrocephalus, Mr. Schulte generously created and endowed The Rudi Schulte Research Institute. Today, RSRI conducts studies to improve treatments for hydrocephalus and other neurological disorders. The Hydrocephalus Association is proud to be working with RSRI to help further this important work.
The purpose of this Request for Applications (RFA) issued by the Hydrocephalus Association is to support one or more high quality, innovative and timely research projects by established investigators that will advance the understanding and control of the normal and abnormal regulation of cerebrospinal fluid (CSF) production, flow, resorption, pressure and pulsatility as they relate to the etiology, progression, and resolution of congenital or acquired forms of hydrocephalus in neonates, children, adults and/or the elderly. The results of this research should lead to translational research resulting in novel diagnostics or interventions (e.g. pharmacologic application, physiological modulation, cellular or gene therapies, recombinant therapeutic approaches, vaccines) to prevent or treat hydrocephalus that will either supplement or replace existing diagnosis and/or treatment with surgical CSF diversion procedures, such as shunt implantation or endoscopic third ventriculostomy (ETV). Particular consideration will be given to novel scientific approaches or to the novel adaptation to hydrocephalus of scientific approaches from other established areas of brain research.
Knowledge of the normal and abnormal physiology of the CSF circulatory system is central to understanding all forms of hydrocephalus. The 2007 NIH hydrocephalus research priorities report states, “There is inadequate understanding of the mechanisms that lead to the initiation, progression, and persistence of neuronal, glial, and vascular dysfunction in hydrocephalus, as well as the mechanisms by which treatment reverses this injury. The application of contemporary methods and techniques in basic neurobiology will provide critical insights into both the injury and recovery mechanisms of hydrocephalus, and we hope that this will lead to improved diagnostic, prognostic, and treatment approaches.” (J Neurosurg (5 Suppl Pediatrics) 2007; 107:345–357.) Recent advances in the understanding of CSF production, flow, resorption, pressure, and pressure pulsatility, and new scientific techniques have made work in this area a strategic priority for the Hydrocephalus Association.
Each year, an estimated 10,000 people in the United States and Canada are diagnosed with hydrocephalus. Hydrocephalus is the abnormal primary enlargement of the cerebral ventricles that results from impaired CSF secretion, circulation, or resorption. Hydrocephalus can develop at any age or stage of life, from intrauterine, fetal development through late life in the elderly. Hydrocephalus may be acute and life-threatening, or subacute or chronic, which if left untreated, can cause permanent brain injury, disability, and sometimes death. Over the past 50 years, the only effective treatments have been shunt placement and endoscopic third ventriculostomy; other surgical and pharmacological interventions have proven ineffective. Over 40,000 shunt-related surgeries occur in the U.S. at a cost of $2 billion per year. More than 50% of implanted shunts require revision within two years, and approximately 8-10% of patients experience infectious complications. Thus, there is a pressing and critical need for innovative research that will lead to improved treatments that will either supplement or replace existing treatment with surgical CSF diversion procedures, such as shunt implantation or ETV.
The regulated production, circulation, and resorption of CSF are integral aspects of normal development and homeostasis in the brain. Since abnormal increase of ventricular CSF volume is a hallmark of hydrocephalus, understanding of normal and altered CSF circulatory physiology is vital for understanding the etiology of hydrocephalus, and the development of effective therapeutic interventions that reverse or prevent progression of hydrocephalus. Many hydrocephalus cases are sporadic, with unclear cellular and molecular etiologies, such as idiopathic aqueductal stenosis or idiopathic normal pressure hydrocephalus. Genetic contribution to rare forms of hydrocephalus has been reported. Hydrocephalus is also associated with other disorders, such as spina bifida, cerebral malformations, and brain tumors. Hydrocephalus is also linked to prenatal or intrauterine events, such as intracranial or germinal matrix hemorrhage, which can produce pathophysiological exposure to blood constituents.
Numerous molecular factors may influence the abnormal accumulation of CSF resulting in hydrocephalus. The production of CSF, which occurs via choroidal and extra-choroidal routes, may be altered during hydrocephalus. Ion channels found on both the basolateral and apical surface of choroid plexus cells transport ions (e.g., Na+, Cl-, and HCO3-) across both membrane surfaces, creating an osmotic gradient that drives the movement of water from blood to CSF. Additionally, aquaporin-1 can contribute to normal CSF production, although its role in hydrocephalus is unclear. Other aquaporins may also be involved. Thus, altered ion and water channels may result in abnormal choroidal CSF production. Dysfunction of other sites of CSF production, such as extra-choroidal ependymal cells, as well as brain parenchyma, may be also contribute to CSF production, though little is known about how these impaired functions arise during hydrocephalus. While excess production has not been demonstrated to be a major cause of hydrocephalus in primates, the relation of CSF production to CSF circulation, transit of CSF substrates, or CSF resoprtion may be critical in feed forward or feedback control mechanisms related to hydrocephalus.
So-called mechanical obstruction to the CSF pathways or outflow may be inadequately understood. Structural changes in the ventricular ependymal lining, foramina of Monro, cerebral aqueduct; foramina of Luschka and Magendie (IVth ventricle outlets), the craniospinal subarachnoid space, the arachnoid villi and cranial lymphatics may all lead to CSF flow constraints and abnormal CSF dynamics. While this type of obstruction has generally been viewed as a simple structural defect, the cellular (e.g., neuronal, glial, vascular endothelial), genetic, or other biological signaling and control mechanisms that result from such obstruction are not well understood. Further, the role of CSF pressure or CSF pressure pulsatility in the development or control of hydrocephalus is inadequately understood. Gene mutations within structural and signaling pathways in animal models can promote hydrocephalus. Alternately, elevated levels of blood-related factors or breakdown components in the CSF have also been associated with these architectural tissue changes and hydrocephalus. Thus, the contribution from both genetic and epigenetic factors to hydrocephalus remains very much an active area of research.
Types of Research and Experimental Approaches
Applications will be accepted from experienced researchers with established research programs in basic, translational or clinical research relevant to hydrocephalus. Awardees will be selected through a competitive, peer-reviewed process. Highest priority will be given to work addressing both understanding and control of physiologic or pathophysiologic mechanisms in hydrocephalus that is likely to lead to changes in diagnostics, therapeutics or clinical interventions within 10 years. Particular consideration will be given to novel scientific approaches or to the novel adaptation to hydrocephalus of scientific approaches from other established areas of brain research.
Examples of applicable research areas include, but are not restricted to: 1) Injury and recovery mechanisms in human research subjects or animal models, 2) Molecular, cellular, genetic and systems physiology, 3) Role of stem cells and neural progenitor cells, 4) Role of inflammation, tissue matrix, blood–brain barrier, 5) Anatomy and physiology of CSF secretion, circulation, resorption and CSF function as it pertains to the development or resolution of hydrocephalus signs and symptoms, 6) Identification and control of critical feed forward or feedback control mechanisms related to hydrocephalus; 7) Identification of biomarkers (i.e., a measurable characteristic that reflects the severity or presence of a disease state; a chemical, physical or biological molecule or physiological signal such as those found in blood, CSF, or in imaging data) characterizing normal and abnormal CSF function and regulation
This RFA is not intended to support the development of medical devices, instrumentation or other commercial applications, nor is it intended to support the development of new animal or ex vivo models of hydrocephalus for the purpose of future research. Applications addressing acute forms of hydrocephalus must show relevance to the prevention of chronic hydrocephalus (e.g. prevention of shunt dependence).
We anticipate supporting 1-3 research projects of 1-3 years duration. We have identified a total pool of $200,000 annually and expect research funding to begin in late 2013. The number of awards made will depend on the quality of the applications received, available funds, and the research priorities determined by the Hydrocephalus Association and its research funding partners.
Potential applicants must complete a letter of intent form January 4, 2013, describing the nature of the proposed project and its relationship to hydrocephalus and identifying their institution.
The form and other application materials are available on the HA website under Research » Research Funding Opportunities » Current Requests for Applications. Completed applications, including letters of institutional commitment, must be submitted in a single PDF document by March 1, 2013. Applicants will receive instructions on uploading applications to the HA secure server in response to their letters of intent.
All inquiries about this RFA should be made via email to [email protected]
Links to supporting documentation for CSF Award Application:
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