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.
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