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

描述（由申请人提供）：由于发现了12个新成员（超出认为存在的3个），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之间的关系（即，它们作为疾病生物标志物的潜在效用），丝氨酸蛋白酶的人激肽释放酶家族近年来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升高的水平，随后已成为已知的最重要的癌症生物标志物。其他成员（例如K6和K8）优先在中枢神经系统（CNS）中表达，并且已知它们的水平在中枢神经系统内神经损伤或炎症的情况下会增加（例如多发性硬化症等炎症性脱髓鞘疾病或脊髓损伤）。新的证据表明，这些激肽释放酶活性的调节在维持CNS的正常和疾病状态中起作用，特别是，抑制K6和K8的活性可能是治疗炎性脱髓鞘的新疗法。然而，关于CNS特异性激肽释放酶是如何调节的知之甚少。这项研究的目的是测试的假设，CNS特异性激肽释放酶的调节部分激活级联反应之间的这个家庭的成员。此外，激肽释放酶蛋白酶系统被假定与CNS中的纤溶酶原激活物（PA）系统相互作用，所述纤溶酶原激活物（PA）系统是在正常和患病状态下调节神经元功能的另一种主要蛋白酶系统。本研究将集中在人K5，K6和K8的前和成熟形式的功能和酶的表征，以及这些激肽释放酶和PA系统之间的假设激活相互作用。待生成的数据将确定CNS内存在的这两个主要蛋白酶系统之间的关键调节相互作用。这些结果将有助于阐明CNS特异性激肽释放酶在炎症性脱髓鞘过程中的作用，并将有助于确定治疗多发性硬化症（MS）和脊髓损伤等疾病的新治疗靶点。该研究计划将支持在现代蛋白质化学，生物物理学和酶学的重要领域培养研究生，并形成他们的博士学位的基础。论文该提案建立在大量初步数据的基础上，这些数据有助于形成有待检验的假设，并使人们相信提案的目标可以实现。与炎性脱髓鞘（例如多发性硬化症）和神经损伤（其还包括疾病进展中的炎性成分）相关的疾病影响数十万美国人。迫切需要针对这些疾病的新疗法，这需要新的科学研究途径。这项拟议中的研究涉及对中枢神经系统中一种新的蛋白酶家族（称为“激肽释放酶”）的研究，其功能似乎与炎症和疾病密切相关。该提案的目标是了解这些蛋白酶是如何控制的，以及如何操纵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.