We are interested in the processes which control cell division and differentiation in the developing embryo. These processes are dependent on the type of embryonic tissue, and must be tightly regulated to ensure the proper size, proportion, and function of each organ. In some cell types, such as skeletal muscle, cell division and differentiation are mutually exclusive: cells first proliferate (by dividing), then cease and initiate differentiation into mature muscle cells. In others, such as cardiac muscle, proliferation and differentiation occur together for a finite period of time. In the adult heart, however, once cells stop proliferating they have extremely limited capacity to resume. In the case of cardiac injury, for example in myocardial infarction or cardiomyopathy, this significantly limits the heart's ability to heal. In contrast, adult skeletal muscle heals readily in the case of injury. These differences in the adult tissue are set in embryonic life. We have identified a family of proteins, the LEK proteins, which appear to be important in the interplay between proliferation and differentiation in both embryonic heart and skeletal muscle. When we prevent mouse LEK protein from being made in a developing heart, the resulting heart is small and thin walled. This effect is intriguing in light of the functions we have demonstrated for LEK proteins in muscle cell proliferation and differentiation. Thus, our model of LEK disruption will be a valuable tool in the study of these processes in the heart. Further, we have identified a role of LEK proteins in a pathway critical for regulating growth and differentiation in all cells, the retinoblastoma protein (Rb) pathway. The Rb proteins are best known as tumor suppressors, that is for their role in controlling abnormal cell proliferation, but they also affect differentiation. We propose to further study the relationship between LEK and Rb proteins, and how they relate to another set of proteins well known to interact with Rb, the E2F proteins. The studies we have designed take advantage of mutations we have created in LEK proteins and expressed in heart and in skeletal muscle cells. With these tools, we can better understand fundamental defects of embryonic cardiac growth related to congenital heart disease. This can direct future therapy, such as stem cell therapy, to someday correct congenital defects at their origin and even stimulate damaged cardiac muscle to heal after injury such as myocardial infarction.

Public Health Relevance

We have identified a family of proteins, the LEK proteins, which are important in the interplay between cell proliferation and differentiation during embryonic muscle development. We propose to study how these proteins interact with others known to control muscle development by using a mouse model with disrupted LEK protein expression. Our ultimate goal is to uncover ways to manipulate muscle cell growth and differentiation in the setting of acquired and congenital heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087050-04
Application #
8271375
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2009-05-15
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$379,913
Indirect Cost
$132,413
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212