Autonomic dysreflexia (AD) is a potentially fatal clinical syndrome that develops after high-level spinal cord injury (SCI) and results in uncontrolled hypertension. Early symptoms may include throbbing headache, profuse sweating or nasal congestion but if left untreated, seizure, pulmonary embolism, stroke or death can occur. The symptoms and frequency of AD can be minimized by removing the stimulus that triggers AD (e.g., full bladder/bowel) but there currently is no way to prevent AD from developing. New data show that besides causing potentially fatal hypertension, recurrent bouts of AD also suppress immune function. This may explain why people with high-level SCI are more susceptible to infection - a leading cause of morbidity and mortality in this patient population.
Three Aims are proposed to answer two main questions. First, is it possible to restore immune function in SCI mice despite persistent AD (Aim 1)? Second, is it possible to block or minimize AD and indirectly improve immune function (Aims 2&3)? Experiments in Aim 1 will use a novel combination of drugs designed to promote immune cell survival in SCI mice with AD. Experiments in Aims 2&3 will try to prevent the development of AD by inhibiting post-injury synaptogenesis in the spinal cord. This will be accomplished using genetic loss of function and pharmacologic techniques (Aim 2) or, alternatively, by using a fetal neural stem cell graft to restore communication between injured supraspinal axons and spinal autonomic circuitry below the injury. If successful, data from Aim 1 could be used to develop new drug regimens that would reduce post-SCI immune suppression, especially in people that experience frequent AD.
Aims 2 and 3 are basic science experiments, designed to reveal novel molecular targets (Aim 2) or establish the feasibility of using neural repair strategies (Aim 3) to prevent the development o AD and restore immune function. Collectively, experiments in this proposal address an unmet need for people living with a SCI, i.e., improving or reversing problems associated with autonomic dysfunction. If successful, data from these experiments could significantly improve quality of life for SCI people and provide significant savings to national health care costs.
Autonomic dysreflexia (AD) is a common but poorly understood complication of spinal cord injury (SCI). AD is a life-long problem and when AD occurs, it can cause severe neurological problems (e.g., seizure, stroke) or even death. Recent data from our lab show that AD also suppresses immune function which may explain why people with high-level SCI become more susceptible to infection - a leading cause of morbidity and mortality after SCI. Experiments in this proposal have two goals. First, we will try to restore immune function after SCI, even if AD occurs. Second, we will try to block or minimize AD, which should indirectly improve immune function. If successful, data from this grant could be used to apply existing therapies or develop new ones to inhibit or block AD and improve quality of life after SCI.
