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

CNS 特异性人激肽释放酶与炎症中 PA 系统之间的相互作用

• 批准号: 7849121
• 负责人: MICHAEL BLABER
• 金额: $ 1.84万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849121
• 关键词: Affect; Alteplase; American; Area; Attention; Biological Markers; Biophysics; Central Nervous System Diseases; Communication; Data; Demyelinating Diseases; Demyelinations; Disease; Disease Progression; Doctor of Philosophy; Elements; Enzymatic Biochemistry; Exhibits; Family; Family member; Goals; Human; Inflammation; Inflammatory; Investigation; Kininogenase; Knowledge; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mentorship; Methods; Multiple Sclerosis; Neuraxis; Neurons; Oral; Patients; Peer Review; Peptide Hydrolases; Plasmin; Plasminogen Activator; Play; Process; Prostate-Specific Antigen; Protein Chemistry; Recombinants; Regulation; Reporting; Research; Research Personnel; Research Proposals; Review Literature; Role; Serine Protease; Spinal cord injury; System; Testing; Thinking; Training; Training Support; Writing; base; central nervous system injury; graduate student; human disease; human kallikrein 5; in vitro testing; injury and repair; insight; member; nerve injury; new therapeutic target; novel; prolyl-proline

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.

描述（由申请人提供）：近年来，由于发现了 12 个新成员（超过了被认为存在的 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用途），丝氨酸蛋白酶的人类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，并随后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会在 CNS 内神经损伤或炎症（例如多发性硬化症或脊髓损伤等炎症性脱髓鞘疾病时发生）情况下增加。新的证据表明，调节这些激肽释放酶的活性在维持中枢神经系统的正常和患病状态中发挥着重要作用，特别是抑制 K6 和 K8 的活性可能是治疗炎症性脱髓鞘的新疗法。然而，人们对中枢神经系统特异性激肽释放酶的调控机制知之甚少。本研究计划的目的是检验中枢神经系统特异性激肽释放酶部分受到该家族成员之间的激活级联调节的假设。此外，激肽释放酶蛋白酶系统被认为与中枢神经系统中的纤溶酶原激活剂（PA）系统相互作用，这是另一种在正常和患病状态下调节神经元功能的主要蛋白酶系统。本研究将重点关注人类 K5、K6 和 K8 的前体和成熟形式的功能和酶学特征，以及这些激肽释放酶和 PA 系统之间假设的激活相互作用。生成的数据将确定中枢神经系统内存在的这两个主要蛋白酶系统之间的关键调控相互作用。该结果将有助于阐明中枢神经系统特异性激肽释放酶在炎症脱髓鞘过程中的作用，并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。该研究计划将支持研究生在现代蛋白质化学、生物物理学和酶学等重要领域的培训，并构成其博士学位的基础。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待检验的假设，并为实现该提案的目标提供了信心。与炎症性脱髓鞘（例如多发性硬化症）和神经损伤（还包括疾病进展中的炎症成分）相关的疾病影响着数十万美国人。迫切需要针对此类疾病的新疗法，这需要新的科学研究途径。拟议的研究涉及对中枢神经系统中一个新的蛋白酶家族（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如何控制此类蛋白酶以及如何操纵这种控制来潜在地治疗中枢神经系统疾病。

项目成果

Activation profiles of human kallikrein-related peptidases by proteases of the thrombostasis axis.

血栓形成轴蛋白酶对人激肽释放酶相关肽酶的激活谱。

• DOI: 10.1110/ps.036715.108
• 发表时间: 2008
• 期刊: Protein science : a publication of the Protein Society
• 作者: Yoon,Hyesook;Blaber,SachikoI;Evans,DMichael;Trim,Julie;Juliano,MariaAparecida;Scarisbrick,IsobelA;Blaber,Michael
• 通讯作者: Blaber,Michael

Substrate specificity and inhibition of human kallikrein-related peptidase 3 (KLK3 or PSA) activated with sodium citrate and glycosaminoglycans.

用柠檬酸钠和糖胺聚糖激活的人激肽释放酶相关肽酶 3（KLK3 或 PSA）的底物特异性和抑制。

• DOI: 10.1016/j.abb.2010.03.022
• 发表时间: 2010
• 期刊: Archives of biochemistry and biophysics
• 影响因子: 3.9
• 作者: Andrade,Douglas;Assis,DiegoM;Lima,AurelioResende;Oliveira,JulianaR;Araujo,MarianaS;Blaber,SachikoI;Blaber,Michael;Juliano,MariaA;Juliano,Luiz
• 通讯作者: Juliano,Luiz

Functional role of kallikrein 6 in regulating immune cell survival.

• DOI: 10.1371/journal.pone.0018376
• 发表时间: 2011-03-28
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Scarisbrick IA;Epstein B;Cloud BA;Yoon H;Wu J;Renner DN;Blaber SI;Blaber M;Vandell AG;Bryson AL
• 通讯作者: Bryson AL

A completed KLK activome profile: investigation of activation profiles of KLK9, 10, and 15.

完整的 KLK 激活组概况：KLK9、10 和 15 激活概况的研究。

• DOI: 10.1515/bc.2009.026
• 发表时间: 2009
• 期刊: Biological chemistry
• 影响因子: 3.7
• 作者: Yoon,Hyesook;Blaber,SachikoI;Debela,Mekdes;Goettig,Peter;Scarisbrick,IsobelA;Blaber,Michael
• 通讯作者: Blaber,Michael

Expression and function of the kallikrein-related peptidase 6 in the human melanoma microenvironment.

• DOI: 10.1038/jid.2011.190
• 发表时间: 2011-11
• 期刊: JOURNAL OF INVESTIGATIVE DERMATOLOGY
• 影响因子: 6.5
• 作者: Krenzer, Stefanie;Peterziel, Heike;Mauch, Cornelia;Blaber, Sachiko I.;Blaber, Michael;Angel, Peter;Hess, Jochen
• 通讯作者: Hess, Jochen