Sophie Astrof, PhD
Philadelphia, PA 19107
(215) 503-5731 fax
MA, Harvard University, Boston
PhD Harvard University, 2000
Massachusetts Institute of Technology, Center for Cancer Research, Cambridge, MA
Associate Professor of Medicine (2013)
Research & Clinical Interests
The main focus of my lab is to understand cellular and molecular mechanisms of cardiovascular development in vertebrates. Heart is the first organ to form during embryogenesis. It's a complex and obviously, a very important organ. Congenital heart defects are among the most common and most severe birth defects in humans, and therefore, understanding basic details about how the heart and the vasculature form would undoubtedly lead to the design of more effective therapies to treat congenital heart defects in the future.
Currently, there are three main areas that the lab is working on. One is to understand the function of tissue microenvironment during the development of the aorta, the pulmonary artery, and the aortic arch arteries (AAAs). These vessels constitute the arterial and pulmonary outflow from the heart, and the proper development of these vessels as well as their proper connectivity with the heart are absolutely crucial. We are interested in understanding how progenitors (also called stem cells) come together and assemble into a functional organ. In the case of blood vessels, endothelial cells comprising the inner layer of a vessel become surrounded by a coat of vascular smooth muscle cells (VSMCs), which are very important for the development and stability of a newly forming vessel. In the case of AAAs and distal portions of the aorta and pulmonary artery, the VSMCs are derived from the cardiac neural crest - a population of progenitor cells originating from the dorsal neural tube of an embryo. The proliferation, survival, migration and differentiation of these progenitors into VSMCs are tightly coupled to signals emitted by embryonic tissues located in the proximity to the cardiac neural crest migration routes. One of the projects in the lab is to understand the nature of these signals. To that end, we are focusing on the role of fibronectin (FN), a large extracellular matrix protein. FN is synthesized by the cardiac neural crest progenitors and by distinct tissues, through which and near which the cardiac neural crest cells migrate, and therefore, we are performing both genetic and cell biological studies to understand the function of cell-autonomous and non cell-autonomous sources of FN during the development of the cardiac neural crest into VSMCs. A complementary major project in this area is to understand how FN signal is received and the downstream consequences of FN signaling to cells. In order to accomplish this, we are using genetics to specifically ablate a major cellular receptor for FN, called integrin α5β1, from specific embryonic tissues. Taken together, the combination of these two approaches will allow us to discern the origin, the role and the downstream effects of specific signals coming from embryonic microenvironments during the development of the cardiac neural crest progenitors into VSMCs.
The second major area of investigation in the lab is to understand the function of tissue microenvironment during development of the vertebrate heart from cardiac progenitors. In mammals, cardiac progenitors are derived from the primitive streak; these cells migrate in the anterior direction on either side of the embryonic midline and come together to form a cardiac tube, which becomes more elaborated as progenitors from distinct embryonic locations are added to it. These cells migrate long distances and come in contact with distinct embryonic environments and signals, and we are using similar approaches as described above to study the signals and their downstream effectors during cardiac morphogenesis.
The third major area of interest in my lab is mechanisms guiding embryonic patterning, and in particular, the development of embryonic left-right axis of asymmetry. Many visceral organs, including the heart, are asymmetrically positioned within the body, and defects in the establishment or maintenance of the left-right body axis can lead to severe congenital abnormalities. We are using both the mouse and the fish as model systems to understand the role of extracellular matrix and its receptors during the development of the left-right asymmetry.
Most Recent Peer-Reviewed Publications
- Endothelium in the pharyngeal arches 3, 4 and 6 is derived from the second heart field
- Neural crest cell-autonomous roles of fibronectin in cardiovascular development
- Fibronectin signals through integrin α5β1 to regulate cardiovascular development in a cell type-specific manner
- Mesodermal expression of integrin α5β1 regulates neural crest development and cardiovascular morphogenesis
- Shape and position of the node and notochord along the bilateral plane of symmetry are regulated by cell-extracellular matrix interactions
- PI3K/Akt1 signalling specifies foregut precursors by generating regionalized extra-cellular matrix
- Fibronectin and integrin alpha 5 play requisite roles in cardiac morphogenesis
- Essential roles of fibronectin in the development of the left-right embryonic body plan
- Fibronectin and integrin alpha 5 play essential roles in the development of the cardiac neural crest
- Fibronectins in vascular morphogenesis
- A system for Cre-regulated RNA interference in vivo
- Multiple cardiovascular defects caused by the absence of alternatively spliced segments of fibronectin
- Heart development in fibronectin-null mice is governed by a genetic modifier on chromosome four
- Decreased plasma fibronectin leads to delayed thrombus growth in injured arterioles
- Direct test of potential roles of EIIIA and EIIIB alternatively spliced segments of fibronectin in physiological and tumor angiogenesis