Preventing autonomic dysreflexia to restore immune function after SCI

描述（由申请人提供）：自主神经反射障碍（AD）是一种可能致命的临床综合征，发生在高位脊髓损伤（SCI）后，导致高血压失控。早期症状可能包括抽动性头痛、大量出汗或鼻塞，但如果不及时治疗，可能会发生癫痫发作、肺栓塞、中风或死亡。通过去除诱发阿尔茨海默病的刺激物（如膀胱/肠满），可以将阿尔茨海默病的症状和发病频率降至最低，但目前还没有办法预防阿尔茨海默病的发生。新的数据显示，除了可能导致致命的高血压外，阿尔茨海默病的反复发作还会抑制免疫功能。这也许可以解释为什么高度脊髓损伤患者更容易感染——这是该患者群体发病率和死亡率的主要原因。提出了三个目标来回答两个主要问题。首先，尽管存在持续性AD，脊髓损伤小鼠是否有可能恢复免疫功能（Aim 1）？第二，是否有可能阻断或减少AD并间接改善免疫功能（目标2和3）？Aim 1的实验将使用一种新的药物组合来促进患有AD的SCI小鼠的免疫细胞存活。Aims 2和3的实验将试图通过抑制脊髓损伤后突触发生来阻止AD的发展。这将通过基因功能缺失和药理学技术来实现（目标2），或者，通过使用胎儿神经干细胞移植来恢复受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，Aim 1的数据可以用于开发新的药物方案，以减少脊髓损伤后的免疫抑制，特别是在经常经历阿尔茨海默病的人群中。Aims 2和3是基础科学实验，旨在揭示新的分子靶点（Aim 2）或建立使用神经修复策略（Aim 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脊髓损伤患者未满足的需求，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著提高脊髓损伤患者的生活质量，并为国家医疗保健成本提供显著节省。

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.