Ju Chen Laboratory In the Department of Medicine

Research Focus

A major focus of the Chen lab is to understand mechanisms by which mutations in cytoskeletal proteins cause cardiac and skeletal myopathy. The cytoskeleton of striated muscle cells is an abundant and highly specialized structure which performs force-generating contraction.
Cytoskeletal components are classified as sarcomeric or extrasarcomeric. The extrasarcomeric network provides a link between adjacent myofibrils to the nuclear envelope and between myofibrils to the sarcolemma/t-tubule and to the extracellular matrix. The Chen lab studies a number of sarcomeric and extrasarcomeric proteins, including Z-disc proteins, intermediate filament proteins, nuclear envelope proteins, and proteins which link the sarcomere to the extracellular matrix. In this manner, the Chen lab is developing a comprehensive understanding of the complex cytoskeletal network required for optimal striated muscle function.
Another major focus of the lab is the study of signaling pathways underlying cardiac hypertrophy and heart failure. Models utilized in the Chen lab include genetically engineered mouse models and human induced pluripotent stem cells (iPSCs) from human patients. Analyses are performed using physiological measurements, and a range of molecular and cell biological techniques.
Below is a list of projects that form the main focus of our research.

Cypher/Zasp - a key protein for Z-disc assembly

Cypher/ZASP Cypher/ZASP is a key component of the sarcomeric Z-disc that is thought to play a critical role in muscle ultrastructure and function by maintaining Z-line integrity during muscle contraction. The functional importance of Cypher is evidenced by the phenotype of global Cypher-null mice, which are postnatal lethal with severe defects in striated muscle, including a congenital form of dilated cardiomyopathy. In addition to its developmental roles, Cypher also plays a critical role in the adult heart, as cardiac-specific deletion in mice causes a severe form of dilated cardiomyopathy resulting in premature adult lethality. Importantly, >15 mutations of ZASP, the human Cypher ortholog, have been identified in patients with cardiomyopathies including dilated cardiomyopathy and skeletal muscle myopathies (specifically termed zaspopathy).
More on Cypher/ZASP >


Nesprin - anchoring the nucleus

Nesprin The family of nesprin proteins are thought to be important for nuclear anchorage and positioning within the cell. To supply further insight into the functions of Nesprin 1, we generated a mouse model in which all isoforms of Nesprin 1 containing the C-terminal SR region with or without KASH domain (hereafter referred to as Nesprin 1−/− mice). We show that Nesprin 1−/− mice are marked by decreased survival rates, growth retardation and increased variability in body weight. We were able to further clarify Nesprin 1's roles in nuclear positioning and anchorage, nuclear membrane structure and cardiac mechanics, as well as investigate Nesprin 1's role in skeletal muscle function, exercise capacity and nuclear mechanics.
More on Nesprin >


FHL1 in skeletal muscle homeostasis and pathology

FHL In 2008, point mutations in the LIM domain protein FHL1 were identified in human patients suffering from Emery-Dreifuss Muscular Dystrophy (EDMD) and dominant-negative Reducing Body Myopathy (RBM) that lead to muscle wasting and cardiac dysfunction. To understand the functional role of FHL1 in the development of these myopathies, we are studying a mouse model in which all isoforms of FHL1 were ubiquitously ablated (FHL1-null). In a second set of experiments we are creating additional mouse lines in which mutations will be introduced through gene targeting in order to mimic mutations identified in human RBM and EDMD, followed by comprehensive molecular, biochemical, histological, and physiological analyses of their skeletal phenotypes.
More on FHL1 >


Naxos disease - Understanding the role of Plakoglobin

naxos In order for the heart to function properly and pump blood efficiently, heart muscle cells must beat and contract in unison. To do this, the heart muscle cells must be tightly connected to each other in order to transmit force (to pump blood). We are studying a protein called Plakoglobin, which is an important linker that connects heart muscle cells to each other. A change in Plakoglobin that leads to an altered version of Plakoglobin that is expressed at lower levels, is the cause of Naxos disease. Naxos disease is a devastating disorder that typically leads to sudden cardiac death before the age of 30. It affects the heart, skin and hair of effected patients. In this study, we have found that if we can increase the levels of Plakoglobin to a certain threshold in mice we can restore their heart function to almost normal. With this in mind, we envisage that Naxos patients may be helped using specific drugs to increase the levels of Plakoglobin.
More on the role of plakoglobin in Naxos disease >


Thymosin beta 4 - small molecule with big impact?

1T44 crystal structure by irobi et al. Thymosin beta 4 (tb4) is a major G-actin sequestering molecule that is thought to play a role in angiogenesis. Promoting cell migration, blood vessel formation, cell survival, cell differentiation, tb4 is thought to be of crucial importance to many cellular and developmental processes. We currently investigate the role of tb4 for heart development.
More on tb4 >

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