New Hydrocephalus Therapies Through Interruption of Lipid Signaling and Inflammatory Pathways Using Novel Drug-Like Compounds
Abstract
Hydrocephalus, also known as water on the brain, is a lifelong medical condition characterized by abnormal build-up of cerebrospinal fluid, enlarged brain cavities, and malformed brains. It is often linked to bleeding in the brain and is one of the most common brain disorders in children. Another form of hydrocephalus is linked to traumatic brain injury, which can happen to individuals of any age; it is possible that these two forms of hydrocephalus share a common origin. Hydrocephalus treatment has relied on neurosurgical management, including use of medical devices called shunts to pipe the excess fluid away from the brain. Shunting alone costs $2 billion per year and has many known complications, such as infection or clogging, which often require multiple brain surgeries over a patient’s lifetime and lifelong monitoring. Improved treatments and cures are desperately needed. This proposal aims to study new ways to prevent bleeding-related hydrocephalus, subsequent neuroinflammation, and improve patient cognitive and motor function. A fat called lysophosphatidic acid, which is released in high amounts into the brain during bleeding, can bind one of its receptors, named LPA1, and cause hydrocephalus. In addition, LPA’s immediate precursor, called lysophosphatidylcholine, or LPC, is converted to LPA via an enzyme called autotaxin. In this proposal, hydrocephalus will be caused by injecting blood or LPC into the brains of mice. A goal is to block autotaxin from making LPA using several chemicals. Other chemicals will be used to block LPA1 receptors. Finally, these compounds will be used alone or in combination with anti-neuroinflammatory chemicals to ensure we find the optimal way to stop hydrocephalus from developing. Just before or after causing hydrocephalus, chemicals that block autotaxin function, LPA receptor function, and neuroinflammation will be delivered into the brain to mimic either preventative or therapeutic treatment. In addition, mouse behavior will be examined using a wide variety of tests to determine if motor or cognitive function can be restored using these compounds. One of the major goals of this study is to optimize combinations of these compounds as a therapy, make sure they are not toxic to mice or people, and to provide enough data to justify larger trials in the future, including clinical trials. This project is innovative since it uses a newly understood LPC- and LPA-induced mechanism of hydrocephalus and a range of chemical tools, along with rigorous examination of behavior, to approach hydrocephalus prevention and cure. This proposal is aimed at making rapid and high-payoff progress in the Fiscal Year 2016 (FY16) Peer Reviewed Medical Research Program topic area of Hydrocephalus. Furthermore, it addresses four of seven FY16 Areas of Encouragement: (1) discovery or validation of novel therapies and therapeutic targets; (2) research on the etiology, prevention, diagnosis, and treatment of post-traumatic hydrocephalus; (3) research on approaches to lessen the impact of brain damage caused by hydrocephalus; and (4) development or validation of improved hydrocephalus model systems. It is hoped that success here will translate to new hydrocephalus treatments for Service members and civilians.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710455
Entities
People
- Jerold Chun
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army