. Spinal cord injury (SCI) is a devastating lifelong affliction that impairs a number of functions including locomotion, breathing, autonomic regulation, and sensation/pain. Unfortunately, there is no current FDA approved therapy for SCI. Therefore, there is a critical need to translate basic science discoveries developed in the laboratory with promising effects after experimental SCI towards human application. SCI elicits an intraspinal inflammatory response comprised of resident glia and infiltrating blood leukocytes. Although subsets of resident and recruited immune cells have been implicated in CNS repair, more than 20 years of experimental data in different animal models of SCI indicate that acute monocyte depletion (MD) is consistently neuroprotective. Further, there are clinically viable drugs, such as clodronate, that can effectively deplete monocytes after SCI. However, a number of fundamental questions must be answered before successful translation including, understanding the extent to which injury level impacts therapeutic efficacy, as well as, understanding the long-term consequences of MD on functional recovery and monocyte repopulation and fate. Therefore, the goals of this proposal are to examine chronic and level-specific functional changes after acute MD using clinically relevant outcomes including pain, autonomic dysreflexia, respiration, and forelimb/hand function. We will study the effects of acute liposome encapsulated clodronate treatment for up to one year in rodent models of cervical and thoracic SCI. Specifically, this grant seeks to:
Aim 1 : evaluate the dose-response effects of acute MD on myelopoiesis, biodistribution, and toxicity;
Aim 2 : determine the efficacy of acute MD on recovery of locomotor, sensory, and autonomic function in chronic SCI rats.
Aim 3 : determine the effects of acute MD on recovery of respiratory motor and forelimb function after cervical SCI. The combined approach of examining the effects of MD after both cervical and thoracic SCI will provide unprecedented preclinical data regarding the effects of monocyte function on sensory, autonomic, pain, and respiratory outcomes. The feasibility of clodronate (aka disodium dichloromethylene diphosphonate) treatment in SCI individuals was reported almost 40 years ago therefore our proposal is significant as data from our studies could be adapted to treat human SCI and is expected to be of critical translational impact.
. There are near 290,000 people in the United States of America that have a spinal cord injury (SCI) (with at least 18,000 new cases each year) many with functional impairment. The main objective of this grant proposal is to investigate a novel therapeutic strategy which modifies the inflammatory response and can potentially lead to protection of the spinal cord after injury, as well as functional recovery. This dose-response experimental approach will be studied in multiple injury levels and functional outcomes, as well as tracked over time and collectively, these studies will lead to better understanding of the impact of inflammatory modification after injury and can potentially lead to improvement in human care and outcomes.
