Preventing autonomic dysreflexia to restore immune function after SCI

描述（由申请人提供）：自主神经反射异常（AD）是一种潜在的致命性临床综合征，在高位脊髓损伤（SCI）后发生，并导致不受控制的高血压。早期症状可能包括搏动性头痛、大量出汗或鼻塞，但如果不及时治疗，可能发生癫痫发作、肺栓塞、中风或死亡。AD的症状和频率可以通过去除触发AD的刺激（例如，全膀胱/肠），但目前没有办法预防AD的发展。新的数据表明，除了引起潜在的致命性高血压外，AD的复发还会抑制免疫功能。这可以解释为什么高级别SCI患者更容易感染-这是该患者人群发病率和死亡率的主要原因。提出三个目标来回答两个主要问题。首先，尽管AD持续存在，SCI小鼠的免疫功能是否可能恢复（目的1）？第二，是否有可能阻断或最小化AD并间接改善免疫功能（目标2和3）？目标1的实验将使用一种新的药物组合，旨在促进患有AD的SCI小鼠的免疫细胞存活。目的2和3中的实验将试图通过抑制脊髓中的损伤后突触发生来预防AD的发展。这将使用遗传功能丧失和药理学技术（目标2）来实现，或者通过使用胎儿神经干细胞移植物来恢复损伤的脊髓上轴突和损伤下方的脊髓自主神经回路之间的通信。如果成功的话，Aim 1的数据可以用于开发新的药物方案，减少SCI后的免疫抑制，特别是在经常发生AD的人群中。目标2和3是基础科学实验，旨在揭示新的分子靶点（目标2）或建立使用神经修复策略（目标3）预防AD发展和恢复免疫功能的可行性。总的来说，本提案中的实验解决了SCI患者未满足的需求，即，改善或逆转与自主神经功能障碍相关的问题。如果成功，这些实验的数据可以显着改善SCI患者的生活质量，并为国家医疗保健成本提供显着节省。

DESCRIPTION (provided by applicant): 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.