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Cooperability
| Project leader |
Salkovic-Petrisic Melita |
| Project co-leader: |
Prof. Rodrigo O. Kuljiš |
| Administering organization: |
University of Zagreb, School of Medicine, Salata 3, HR 10 000 Zagreb, Croatia
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| Partner Institution/Company: |
The University of Texas Medical Branch at Galveston, |
| Grant type: |
1B |
| Project title: |
Cytopathological characterization of the brain in a rat model of sporadic Alzeimer disease |
| Project summary: |
Alzheimer’s disease (AD) is a uniquely human condition that is very difficult to study. There are many reasons for such difficulties, including the fact that the most rigorous analytical techniques are ethically unacceptable in patients, and that postmortem human tissue is inadequate for many additional methodologies. These challenges could be mitigated employing a suitable animal model, but almost all such models consist on distinctly unnatural genetically engineered versions of the most infrequent (familial and very atypical) forms of the disease. This is a project to employ a battery of light- and electron microscopic cytopathological methods in a unique rat model of sporadic AD, i.e. by far the most common clinical form of the disorder (ca. 98%), that was developed by the Project Leader by intraventricular injection of streptozotocin (STZ), and agent that is selectively toxic to particular brain cells and causes changes that resemble AD. In fact, this model has been shown repeatedly to exhibit behavioral and molecular alterations resembling AD, and some cerebral lesions strongly suggesting — but not proving — that there are parallels with AD histopathology. Such converging lines of evidence indicate very clearly that an in-depth cytopathological characterization is both an essential and indispensable step to further develop this model for useful translational applications, and to analyze in detail the mechanisms underlying a host of AD-like changes in the brain. Accordingly, we will employ an array of methods to reveal amyloid-containing, senile plaque-like and neurofibrillary tangle-like lesions, as well as neuronal loss and compare such lesions with an extensive collection of AD (i.e. human) and mouse material that contains such lesions, to test the hypothesis that the STZ-treated rats exhibit progressive AD-like pathology as time after injection increases. The null hypothesis, which is not supported by the limited histopathological analyses so far, will be that there are no AD-like lesions. In full compliance with the guidelines for the Unity Through Knowledge Fund, this project is also designed to support basic and applied scientific research to create new knowledge and to make competition possible internationally, to directly and indirectly strengthen the Croatian economy and biomedical infrastructure. This includes the laying out of the foundations to extend this work beyond the term of support requested, to employ a very well characterized rat model of sporadic AD in a potentially large array of truly innovative translational technology applications to conquer AD and related disorders (e.g. Parkinson’s disease and Lewy body dementia). |
| Hrvatski sažetak: |
Alzheimerova bolest (AB) jedinstvena je bolest koju je vrlo teško istraživati. Razlozi tome su višestruki, uključujući činjenice da je većina analitičkih metoda neetična za primjenu u bolesnika te da je postmortalno tkivo ljudskog mozga neprikladno za neke metodološke postupke. Ove se poteškoće mogu zaobići uporabom prikladnih životinjskih modela, ali gotovo svi takvi modeli temeljeni su na neprirodnom genetskom inžinjeringu te stoga predstavljaju model za rijetke (familijarni oblik) i atipične oblike bolesti. Ovaj će projekt koristiti bateriju citopatoloških metoda svjetlosne i elektromikroskopije u istraživanju jedinstvenog štakorskog modela sporadične AB, najčešćeg kliničkog oblika ove bolesti (približno 98%), razvijenog od strane Glavnog istraživača putem intracerebroventrikularne primjene streptozotocina (STZ-icv), tvari selektivno toksične za specifične stanice mozga, što dovodi do promjena sličnih AB. Ovaj model pokazuje reproducibilne molekularne i bihevioralne promjene slične onima u AB, što upućuje ali i ne dokazuje postojanje paralele s histopatološkim nalazom u AB. Ovi konvergentni dokazi jasno upućuju da je dublja i opsežnija citopatološka karakterizacija ključna i prijeko potrebna za daljnji razvoj ovog modela i njegovu uporabu u translacijskoj medicini, te detaljno proučavanje mehanizama u mozgu koji dovode do AB. U tu svrhu upotrijebit ćemo skup metoda za otkrivanje promjena poput amiloidnih senilnih plakova, neurofibrilarnih snopića i gubitka neurona te ih usporediti s promjenama u kolekciji tkiva mozga miša i čovjeka, kako bi se ispitala hipoteza da STZ-icv model štakora s vremenom razvija progresivnu patološku sliku sličnu onoj u AB. Nul hipoteza, koju ne podupiru rezultati dosadašnjih malobrojnih istraživanja, bi bila da ovaj model ne razvija promjene slične onima u AB. U skladu s načelima Unity Through Knowledge Fund, ovaj projekt je također osmišljen na način da podupre temeljna i primijenjena znanstvena istraživanja, dovede do novih saznanja i međunarodne kompetitivnosti te izravno i neizravno ojača hrvatsku ekonomiju i biomedicinsku infrastrukturu. To uključuje postavljanje temelja za suradnju širih razmjera i uporabu dobro karakteriziranog štakorskog modela sporadične AB u primjeni potencijalno šire inovativne translacijske tehnologije u borbi protiv AB i sličnih bolesti ( npr. Parkinsonove bolesti i Lewy body demenciji). |
| Amount requested from UKF: |
1.115.000,00 HRK |
| Amount of matching funding: |
294.000,00 HRK |
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