Heikenwälder
Fakultäten » Medizinische Fakultät » Neuropathologie, Institut für » Prof. Dr. Adriano Aguzzi » Heikenwälder
Completed research project
| Title / Titel | Understanding human prions strains by humanizing the immune system of mice | ||
|---|---|---|---|
| Abstract (PDF, 14 KB) | |||
| Summary / Zusammenfassung | Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases affecting both humans and a large variety of animals. Surprisingly, the immune system has emerged as a key modulator of TSEs in animals as well as in humans over the last decade. Indeed, prion infectivity was found in lymphoid organs of various animals [e.g. scrapie sick sheep and goat; elk and deer suffering from chronic wasting disease (CWD) terminal cattle suffering from bovine spongiform encephalopathy (BSE)] and variant Creutzfeldt-Jakob patients (vCJD). Only recently, disease-associated prion protein (PrPSc, encoded by the Prnp gene) was also found in lymphoid organs and muscles of sporadic Creutzfeldt-Jakob patients (sCJD). Up to date the potential pathogenicity of xenotropic prion strains for humans (e.g. scrapie in sheep and goat; CWD in elk and deer) as well as the molecular and cellular preconditions for human to human transmission are unclear. In a first set of projects, I will investigate the cellular and molecular phenomena controlling the transmission of prion diseases from farm animals to humans. Ethical constraints prevent most functional analyses of the neuroimmunological aspects of TSEs in humans. By combining transgenesis and xenotransplantation, I propose to create an accurate animal model that will circumvent such constraints. The immune system of immune compromised mice and deficient for the gene encoding the prion protein, will be reconstituted with CD34+ hematopoietic stem cells derived from the umbilical cord blood of healthy human newborns. Human hematopoietic cells will carry each of the common polymorphisms of the prion gene (e.g. 129M, 129V) and reconstitute the murine immune system. As prions can replicate in the immune system, this protocol of hematopoietic reconstitution will enable reconstituted lymphoreticular organs of recipient mice to act as "humanized" bioreactors, in which human prions will be able to replicate without encountering a species barrier. Additionally, I plan to backcross "humanized" mice to mice that transgenically express different human Prnp polymorphisms (e.g. 129M or 129V) in the brain and the stroma. By this approach we will be able to test various different prion strains for their tropism in a human lymphoid system and most importantly, elucidate the mechanisms of prion transmigration from the periphery into the CNS (a process defined as “neuroinvasion”). With these tools we will be able to directly probe the significance of neuroimmune phenomena in the pathogenesis of sCJD and vCJD. Furthermore, we will test the potential pathogenicity of xenotropic prion strains for humans (e.g. scrapie, CWD). In addition to advancing prion science, the above described strategy will yield an extremely sensitive, ethically acceptable and reasonably rapid test for human prion infectivity. |
||
| Publications / Publikationen | prion disease, TSE, immune system | ||
| Project leadership and contacts / Projektleitung und Kontakte |
|
||
| Other links to external web pages | http://www.neuropathologie.usz.ch/ | ||
| Funding source(s) / Unterstützt durch |
Foundation Bonizzi-Theler-Stiftung |
||
| Duration of Project / Projektdauer | Jul 2006 to Jun 2008 |