Interactions between CNS-specific human kallikreins and the PA system in inflamma

描述(由申请人提供)：近年来，由于发现了12个新成员(超过3个被认为存在的成员)，以及激肽释放酶家族不同成员水平的增加或减少与各种疾病状况(即它们作为疾病生物标志物的潜在用途)之间的关系，人类激肽释放酶家族获得了相当大的关注。例如，激肽释放酶3(K3；或前列腺特异性抗原)在前列腺癌患者中表现出高水平，随后成为已知的最重要的癌症生物标志物。其他成员(如K6和K8)优先在中枢神经系统(CNS)表达，已知它们的水平会增加中枢神经系统内的神经损伤或炎症(如多发性硬化症或脊髓损伤等炎症性脱髓鞘疾病)。新的证据表明，这些激肽释放酶活性的调节在维持中枢神经系统的正常和疾病状态中都起着作用，特别是抑制K6和K8的活性可能是治疗炎性脱髓鞘的一种新方法。然而，关于中枢神经系统特异性激肽释放酶是如何被调控的，人们知之甚少。这项研究建议的目的是检验这一假设，即中枢神经系统特异性激肽释放酶在一定程度上受该家族成员之间的激活级联调控。此外，激肽释放酶系统被认为与中枢神经系统中的纤溶酶原激活物(PA)系统相互作用，纤溶酶原激活物(PA)系统是另一个调节正常和疾病状态下神经元功能的主要蛋白酶系统。这项研究将集中于人类K5、K6和K8的前体和成熟型的功能和酶特性，以及这些激肽释放酶与PA系统之间假想的激活相互作用。将要产生的数据将确定中枢神经系统中存在的这两个主要蛋白酶系统之间的关键调控相互作用。这些结果将有助于阐明中枢神经系统特异性激肽释放酶在炎性脱髓鞘过程中的作用，并将有助于寻找治疗多发性硬化症(MS)和脊髓损伤等疾病的新靶点。该研究计划将支持对现代蛋白质化学、生物物理学和酶学等重要领域的研究生的培训，并构成他们博士论文的基础。该提案建立在大量初步数据的基础上，这些数据帮助形成了待检验的假设，并提供了对该提案的目标能够实现的信心。与炎症性脱髓鞘相关的疾病(例如多发性硬化症)和神经损伤(也包括疾病进展中的炎性成分)影响着数十万美国人。迫切需要针对这类疾病的新疗法，这需要新的科学研究途径。这项拟议的研究涉及对中枢神经系统中一种新的蛋白水解酶家族(称为“激肽释放酶”)的研究，该家族的功能似乎与炎症和疾病密切相关。该提案的目标是了解这种蛋白水解酶是如何被控制的，以及如何控制这种控制来潜在地治疗中枢神经系统疾病。

DESCRIPTION (provided by applicant): The human kallikrein family of serine proteases has gained considerable attention in recent years due to the discovery of 12 new members (beyond the 3 that were thought to exist), and the relationship between the increase or decrease in levels of different members of the kallikrein family and various disease conditions (i.e. their potential utility as biomarkers of disease). For example, kallikrein 3 (K3; or prostate-specific antigen) exhibits elevated levels in patients with prostate cancer and subsequently has become the most important cancer biomarker known. Other members (e.g. K6 and K8) are preferentially expressed in the central nervous system (CNS) and their levels are known to increase in conditions of nerve injury or inflammation within the CNS (such as occurs with inflammatory demyelinating diseases like Multiple Sclerosis, or spinal cord injury). New lines of evidence indicate that regulation of the activity of these kallikreins plays a role in the maintenance of both normal and diseased states of the CNS, and in particular, that inhibition of the activity of K6 and K8 may be a novel therapy to treat inflammatory demyelination. However, very little is understood regarding how CNS-specific kallikreins are regulated. The purpose of this research proposal is to test the hypothesis that CNS-specific kallikreins are regulated in part by activation cascades between the members of this family. Additionally, the kallikrein protease system is postulated to interact with plasminogen activator (PA) system in the CNS - another major protease system that regulates neuronal function in normal and diseased states. This study will focus upon the functional and enzymatic characterization of pro- and mature forms of human K5, K6 and K8, and the hypothesized activation interactions between these kallikreins and the PA system. The data to be generated will identify key regulatory interactions between these two major protease systems present within the CNS. The results will help to elucidate the role of CNS-specific kallikreins in the process of inflammatory demyelination, and will help to identify novel therapeutic targets for the treatment of diseases such as Multiple Sclerosis (MS) and spinal cord injury. The research proposal will support the training of a graduate student in important areas of modern protein chemistry, biophysics and enzymology, and form the basis of their Ph.D. thesis. The proposal builds upon a substantial body of preliminary data that has helped to form the hypothesis to be tested, and provides confidence that the goals of the proposal can be achieved. Disease associated with inflammatory demyelination (e.g. Multiple Sclerosis) and nerve injury (which also includes an inflammatory component in the progression of disease) affects hundreds of thousands of Americans. Novel treatments for such diseases are desperately needed, which require new avenues of scientific investigation. The proposed research involves a study of a new family of proteases (known as "kallikreins") in the central nervous system whose function appears to be closely associated with inflammation and disease. The goals of the proposal are to understand how such proteases are controlled and how this control can be manipulated to potentially treat diseases of the central nervous system.