Preventing autonomic dysreflexia to restore immune function after SCI

描述(申请人提供)：自主神经反射障碍(AD)是一种潜在的致命的临床综合征，在高位脊髓损伤(SCI)后发展，并导致无法控制的高血压。早期症状可能包括阵发性头痛、大量出汗或鼻塞，但如果不治疗，可能会发生癫痫、肺栓塞、中风或死亡。通过移除触发AD的刺激(例如，充分的膀胱/肠道)，可以最大限度地减少AD的症状和频率，但目前还没有办法阻止AD的发展。新的数据显示，除了导致潜在的致命高血压外，反复发作的AD还会抑制免疫功能。这可能解释了为什么患有高水平脊髓损伤的人更容易受到感染--这是这种患者群体中发病率和死亡率的主要原因。提出了三个目标，以回答两个主要问题。首先，尽管存在持续性AD，SCI小鼠的免疫功能是否有可能恢复(目标1)？第二，是否有可能阻止或减少AD并间接提高免疫功能(目标2和3)？目标1的实验将使用一种新的药物组合，旨在促进患有阿尔茨海默病的SCI小鼠的免疫细胞存活。AIMS 2和AIMS 3的实验将试图通过抑制损伤后脊髓中的突触生成来防止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来恢复受损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，来自AIM 1的数据可以用于开发新的药物方案，减少脊髓损伤后的免疫抑制，特别是在经常经历AD的人中。目标2和目标3是基础科学实验，旨在揭示新的分子靶点(目标2)或确定使用神经修复策略的可行性(目标3)以防止AD的发展和恢复免疫功能。总的来说，这项提案中的实验解决了脊髓损伤患者尚未得到满足的需求，即改善或逆转与自主神经功能障碍相关的问题。如果成功，来自这些实验的数据可以显著提高SCI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.