 |
|
|
|
|
 Kenneth R. Chien, MD, PhD |
||
|
||
|
||
|
||
| Lab Overview | About | Science | Stem Cell Program | Faculty Directory | ||
|
||
|
||
|
||
|
Science
Goal: to clone patient-specific master human cardiovascular stem cells that will allow the identification of genetic modifiers, molecular pathways, biologically targeted drugs, and regenerative therapy for heart disease and related disorders Cardiovascular disease is the leading cause of mortality in the U. S., and is a growing global health problem in developing nations. In the U.S. alone, approximately 71 million people are affected by coronary heart disease, which costs society $403.1 billion in 2003. At the same time, heart failure is the leading cause for hospitalization, and the demand for heart transplantation continues to vastly exceed the availability of donor hearts. While there is an array of medications and other treatments for heart disease, none of them are cures, and the course of the disease is relentlessly progressive. In this regard, a number of clinical trials have attempted to regenerate heart muscle after a heart attack through the use of bone marrow stem cells, but recently it is becoming clear that there is little or no evidence of muscle regeneration and the clinical results have been largely disappointing. There is now an urgent need to identify the most promising cardiovascular stem cells for achieving true muscle regeneration. At the same time, the technology of human ES cells is moving as such a rapid pace that we are in a position to develop patient specific master cardiovascular stem cells that have genetic mutations that lead to important forms of heart disease. By utilizing these stem cells as model systems, it should be possible to identify the molecular pathways that drive heart disease, and to develop specific, targeted therapy for rare and common forms of heart disease, by directly screening for both genes and drugs that can block the onset of the disease at a cellular level. At the same time, we plan to rigorously study the potential of master cardiovascular stem cells for regeneration of heart muscle and other important heart tissues, including the formation of coronary arterial blood vessels. To achieve these worthy, but ambitious goals, the Stem Cell Biology Program at the CVRC has forged relationships with the Harvard Stem Cell Institute to bring together a cadre of leading basic scientists and cardiovascular clinicians at internationally elite institutions, including the Massachusetts General Hospital (MGH), Children's Hospital Boston (CHB), Beth Israel Deaconess Medical Center (BIDMC), Harvard University's Faculty of Arts and Sciences (FAS), and the Broad Institute. The diversity of backgrounds and research foci across this broad talent pool, and the sharing of knowledge hold the potential to accelerate the pace of work in this field and enable researchers to uncover and correct the causes of heart disease. The HSCI Cardiovascular Disease Program focuses on what are called cardiac progenitor cells, recently discovered by Kenneth Chien's lab at MGH (Nature, 2005), that develop into mature, fully functional cardiac muscle cells. Yet insights into cardiac repair have been hampered by a major hurdle: cardiac progenitor cells grow in a mixed population of cell types, and are difficult to isolate because we do not yet know what their specific identifying markers may be; and this absence of identifying markers has left the field without a genealogy tree of cardiac cell developmental processes. Therefore, the Cardiovascular Disease Program's main goals are: Identifying specific cell markers The first step in assessing the regenerative capacity of cardiac progenitor cells is to identify and unravel the nature of these cells. Focusing on recently identified cell groups, researchers are isolating the signals and steps of in the development of a progenitor cell into a mature heart muscle cell. This process involves the use of tools and techniques such as transcriptional (signal) profiling and antibody generation. In addition, investigators are using colored tags to track the migration, incorporation, and function of these cells within the cardiovascular system. Building a genealogy tree In order to design effective cell replacement treatments, researchers must first learn how a normal cardiac progenitor cell develops into a mature heart muscle cell. Creating a genealogy tree (called a lineage map) will provide investigators with the pathways particular cells can take and indicate where they may degenerate. RNAi, chemical screening, and microarray analysis are some of the technologies used. Developing patient-specific human ES cell lines By using Nuclear Transfer (NT) to create human ES cell lines carrying specific genes responsible for heart disease, HSCI researchers will provide models with which to study certain properties of these cells. They will be able to study the phenomena of homing, asking whether stem cells migrate to the correct location (niche) within the body; of engraftment, seeking to learn if these cells establish themselves within that niche; of maturation, following the development of progenitor cells to maturity; and finally, of function, to learn if these mature cells behave like cardiac and vascular cells. Because so many HSCI researchers are based at clinical institutions, the Cardiovascular Disease Program has access to a large, well-characterized patient population. This represents a unique opportunity for access to neonatal and adult human heart tissues and cells for studies with cardiac progenitor cells. Collaborations: Dr. Kenneth R. Chien is the Director of the Stem Cell Biology + Therapy Program and works closely with the Harvard Stem Cell Institute. back to top |
||
|