Grant: Operating Grant

Several years ago we discovered that a calcium-binding protein, calreticulin, initially found in a skeletal muscle, is also present in cardiac and smooth muscle and in non-muscle cells. In addition, evidence has been accumulating as to suggest that calreticulin is more than a calcium-storage protein, since it modulates gene transcription in response to steroid hormones and it is involved in regulation of cell adhesiveness. Genetic knockout of calreticulin prevents embryonic heart from developing. Using transgenic mice expressing green fluorescent protein under control of the calreticulin promoter we have shown that the calreticulin gene is transiently activated in the developing heart. In the adult, calreticulin abundance increases in cardiac hypertrophy. On the other hand, targeted overexpression of calreticulin in the heart leads to bradyarrhythmia and complete heart block, followed by sudden death. Hence, the protein plays an important role both in cardiac development and pathology. Nonetheless, almost nothing is known about function of calreticulin in cardiomyocytes. Not even its precise distribution in the heart is known. Therefore, the general objective of my research is to unravel cell role of calreticulin in heart development and function, while the most immediate objective of this proposal is to the cell biological basis for the role of calreticulin in cardiomyocyte differentiation and function.