Aguzzi
Fakultäten » Medizinische Fakultät » Neuropathologie, Institut für » Prof. Dr. Adriano Aguzzi » Aguzzi
Completed research project
| Title / Titel | Diagnostic, Prognostic, and Therapeutically Relevant Prion Co-Factors: An Approach Based on Functional Genomics | ||||
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| Abstract (PDF, 14 KB) | |||||
| Summary / Zusammenfassung | Prion diseases (also called transmissible spongiform encephalopathies, or TSEs) include Creutzfeldt-Jakob disease (CJD) and kuru in humans, mad cow disease (BSE) in cattle, and chronic wasting disease (CWD) in deer and elk. All of these diseases lead to brain damage and to the inevitable death of affected individuals. The infectious agent is termed prion, and its only known component is an abnormally folded protein called PrPSc, which is thought to multi-ply by imparting its three-dimensional structure onto a normal host protein called PrPC. Although some PrPC-interacting proteins have been discovered, the normal function of PrPC in the body remains essentially obscure. Likewise, the mechanisms by which PrPSc causes brain damage are not understood. These two questions may be related to each other, and therefore their combined understanding is important to develop diagnostic and therapeutic procedures. In a first approach, we propose to use highly sensitive, state-of-the art methodologies (collec-tively termed "functional genomics") to identify proteins that network with PrPC, PrPSc, or a similar protein called Dpl. In specific aim 1, we will go after the networking proteins directly us-ing “mass spectrometry” (a method that allows to directly measure size, charge, and sequence of proteins). In specific aim 2, we will exploit the tremendous power of genetic analysis in the fruit fly Drosophila to identify genes that interact with prions and are involved in brain damage. The latter approach has an excellent track record of usefulness for the study of other brain dis-eases, such as Parkinson’s, Alzheimer’s and Huntington’s disease. The various candidate molecules identified in specific aims 1-2, will be validated in animal models (specific aim 3). One approach will consist of introducing the newly discovered genes into “transgenic” mice, and another will consist of searching for changes in concentration of candidate molecules in body fluids. In specific aims 4-5, we propose to apply proteomics to the early diagnosis of TSEs. Currently, a definite diagnosis of prion disease can only be made after the death of the affected individual by careful analysis of the affected brain tissue. We intend to develop proteomics-based meth-ods for the sensitive detection and quantification of PrPSc and/or other TSE-specific markers. We intend to detect these disease indicators in urine, which is an easily accessible body fluid, and thus enhance early diagnosis of prion diseases. The sensitivity of modern instrumentation allows routine measurements of 10-15 moles of protein, which should detect very low amounts of prions and thus effectively lower the risk of exposure to TSEs. Specific aims 6-7 will be devoted to the study of prion strains. Strains are of crucial importance to public health, since some of them are lethal to humans but other may be less dangerous. For example, there is strong evidence that the BSE strain of prions is very dangerous for humans, whereas sheep scrapie prions are probably much less dangerous. For the management of the CWD problem in the US, it is extremely important to learn whether CWD prions have strain properties similar to those of BSE, or to scrapie, or are completely different from any of the hith-erto known prion strains. We will make use of an array of modern techniques to better define measurable properties of strains in all currently existing prion diseases, including CJD, CWD, BSE, and scrapie. We will take advantage of an extensive bank of human and animal prion-infected tissues that we have established at our Institute over the last decade in the framework of a Swiss National Prion Disease Research program. |
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| Keywords / Suchbegriffe | prion diseases, TSE, functional genomics, proteomics, mass spectometry, prion recepors, prin pathogenesis, prin detection, prion diagnostics | ||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
Other Public Sources (e.g. Federal or Cantonal Agencies) Department of Defense (USA) |
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| Duration of Project / Projektdauer | Jul 2003 to Jul 2007 |