Genetic mutation in certain genes causes familial forms of amyotrophic lateral sclerosis (ALS). Toward understanding the mechanisms of a disease mutation, a critical step is creating a desirable model for research. Whereas cellular models are important for testing some aspects of disease mechanisms, animal model is essential for unraveling the mechanisms of complex neurodegeneration because findings from in vitro studies do not always translate to live animals. When a pathogenic mutation exhibits a dominant trait, animal models are often created by randomly inserting transgenes into host genome, incurring gene-insertional mutation and position effects. The levels and patterns of transgene expression largely depend on position effects and vary from line to line even when two lines carry the same copy of transgenes. The best control for genetic model is the transgenic strain that expresses wildtype form of a disease gene but develops no phenotypes observed in mutant transgenic strain. It is unlikely to obtain two lines that express wildtype and mutant proteins at similar levels and patterns. Authentic mechanisms are often obscured by the drawbacks of traditional transgenics. To avoid gene insertional mutation and unify position effect among individual lines, we will insert single copy of transgene at predetermined intergenic locus and will combine it with Tet-inducible system to amplify transgene expression such that plausible phenotypes can be induced within a rat's lifetime. Using these novel rats, we will examine the mechanisms of hnRNPA1 pathogenesis at a systematic level. We will validate the efficacy of this novel transgenic approach in disease induction by comparing phenotypic expression with those observed in the knockin rats that express disease gene at physiological levels and in its intrinsic patterns.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS089701-01
Application #
8798090
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gubitz, Amelie
Project Start
2014-08-15
Project End
2019-05-31
Budget Start
2014-08-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$339,063
Indirect Cost
$120,313
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107