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[Genetically modified animal models in cardiovascular research]
F Dalloz1, H Osinska, J Robbins
1Department of Pediatrics, Division of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, USA.
Insights
Altering the heart's protein complement using gene targeting and transgenesis allows researchers to study the functional impact of specific proteins. This approach helps define therapeutic targets for heart diseases by examining molecular and physiological consequences.
Area of Science:
- Molecular Medicine
- Cardiovascular Biology
- Genetics
Context:
- Cellular and organ function are fundamentally determined by their specific protein complements.
- Alterations in protein pools are observed during normal development and in various pathologies, particularly in the heart.
- Congenital heart diseases exhibit distinct shifts in cardiac motor proteins.
Purpose:
- To establish models for studying pathogenic processes longitudinally by directing the heart to stably synthesize candidate proteins.
- To determine if a protein's presence directly or indirectly causes observed effects, aiming to identify potential therapeutic targets.
- To understand the mechanism and function of different mutated proteins and protein isoforms by precisely altering the heart's protein complement.
Summary:
- Gene targeting and transgenesis in mice enable modification of the mammalian genome and cardiac motor protein complement.
- Directing engineered protein expression to the heart allows for remodeling of the cardiac protein profile.
- This enables the study of consequences of single genetic manipulations at multiple biological levels under normal and stress conditions.
Impact:
- Provides a method to establish both mechanism and function of different mutated proteins and protein isoforms.
- Facilitates the study of molecular, biochemical, cytological, and physiological consequences of genetic manipulation in the heart.
- Aids in defining potential therapeutic targets for heart conditions by elucidating protein function in disease models.
Abstract:
It is a basic tenet of molecular and clinical medicine that specific protein complements underlie cell and organ function. Since cellular and ultimately organ function depend upon the polypeptides that are present, it is not surprising that when function is altered changes in the protein pools occur. In the heart, numerous examples of contractile protein changes correlate with functional alterations, both during normal development and during the development of numerous pathologies. Similarly, different congenital heart diseases are characterized by certain shifts in the motor proteins. To understand these relationships, and to establish models in which the pathogenic processes can be studied longitudinally, it is necessary to direct the heart to stably synthesize, in the absence of other peliotropic changes, the candidate protein. Subsequently, one can determine if the protein's presence causes the effects directly or indirectly with the goal being to define potential therapeutic targets. By affecting the heart's protein complement in a defined manner, one has the means to establish both mechanism and the function of the different mutated proteins of protein isoforms. Gene targeting and transgenesis in the mouse provides a means to modify the mammalian genome and the cardiac motor protein complement. By directing expression of an engineered protein to the heart, one is now able to effectively remodel the cardiac protein profile and study the consequences of a single genetic manipulation at the molecular, biochemical, cytological and physiologic levels, both under normal and stress stimuli.