Research :
HIF-1 Overexpression
A better understanding of angiogenesis, the induction of new blood vessel growth, has the potential to improve treatment of many diseases.
We are especially interested in myocardial ischemia. Hypoxia inducible factor (HIF-1) is a transcription factor that directs the genomic response to hypoxia.
This protein is rapidly degraded under normal levels of oxygen. When oxygen levels decrease, the protein accumulates and directs a cascade of gene regulation that determines the response to hypoxia.
In our studies we use a modified HIF-1 cDNA in which the degradation mechanisms no longer operate, resulting in constitutive activation of the protein.
We have inserted this mutated form into a tet regulated transgenic line and are thus able to express active HIF-1 in a normoxic environment in the hearts of adult mice.
This is an advance over previous studies that have either examined the actions of HIF in vitro, or in transgenic models that modify activity during development.
We are evaluating the phenotype of HIF-1 expression with transcriptional, histological and physiological determinations.
Additionally, we are evaluating the ability of this over-expression to ameliorate tissue death following myocardial infarction.
Here, the heart on the left is wild-type, and the right heart is from a mouse in which stable HIF-1 protein was expressed for two weeks. Notice the enlarged epicardial vessels, and dilation, of the HIF-1 heart.
Endothelial Responses to Cardiovascular Stress
Ongoing studies within our laboratory focus on a comprehensive examination of endothelial transcript-level responses to cardiovascular stress using relevant and well-defined mouse models of human pathophysiology.
Currently, our models include air pollution (diesel exhaust), atherosclerosis and diabetes. Previous studies in our laboratory of the response to lipopolysaccharide and environmental side-stream tobacco smoke revealed
changes in endothelial transcripts relating to host-defense and vasoregulation, respectively.
An authentic assessment of transcript-level changes is performed in vivo using mice which express green fluorescent protein exclusively within their endothelium (see figure on right).
Proteolytic digestion of cardiovascular tissues followedby FACS sorting allows isolation of these cells to high purity. Subsequent application of DNA microarray technology then allows
measurement of the transcript-level responses occurring within our models, using highly representative, long oligonucleotide microarrays.
Elucidating the Role of Endothelin-1 in the Heart
Endothelin (ET-1) is a hormone known primarily as a potent vasoconstrictor. ET receptor antagonists have been investigated for treatment of heart failure and are being used to treat pulmonary arterial hypertension.
We are interested in the role of endothelin-1 in the heart. Using Cre-LoxP technology, we have developed cardiac-specific knock-outs of the peptide and its receptors to elucidate the function of this signaling axis in cardiac tissue.
We have found that endogenously expressed ET-1 appears to protect cardiac myocytes as they age or are subjected to hemodynamic stress.
As demonstrated in the figure, mice with cardiac knock-out of ET-1 show cardiac dilation with age, decreased ventricular function by echocardiography,
and histological evidence of myocyte hypertrophy, heterogeneity and fibrosis, all typical for a dilated cardiomyopathy.
Ultrasound Targeted Microbubble Destruction (UTMD)
though protein and gene therapy strategies are promising, there has yet to be developed a highly efficient, reliable in vivo method for local delivery.
We have helped to develop a technique, termed ultrasound targeted microbubble destruction (UTMD), that allows for local delivery of moieties to specific regions in vivo.
Microbubbles, which are composed of a high molecular weight gas surrounded by a polymer, protein, or lipid shell, became popularized in the 1990’s as contrast agents for ultrasonic imaging of the cardiovascular system.
An ultrasonic signal of the correct strength can disrupt the bubbles, which allows for volumetric flow studies within vessels.
We have attached both plasmids and proteins to microbubbles, injected them into rats, and obtained efficient delivery to target organs by destroying the microbubbles with a properly guided ultrasonic signal.
Applications of this technology are vast, and a few of those currently being investigated include HIF-1 delivery to ischemic tissue, insulin delivery to pancreatic islet cells, and gene expression modification upon endothelial tissue.
Here, a microbubble is destroyed by an ultrasonic signal, thus releasing the attached moiety into the surrounding tissue (Physics Today, December 2005).
Human Genetics
Phenotypic differences between different human populations are often explained by genetic variation.
It is likely that susceptibility to cardiovascular disease, and to the illnesses, such as hypertension and diabetes, that contribute to heart disease, have meaningful genetic components.
We expect that the understanding of genetic variation in various populations will contribute to the mechanistic understanding of how cardiovascular disease develops, and why it affects different ethnic groups in distinct ways.
We are analyzing genomic information from various populations for shifts in allelic frequencies that will lead to a further comprehension of phenotypic variation and disease susceptibility.
We are also interested in any families that have a high frequency of cardiovascular illness or even more than a single case of unusual cardiac disease.
Here, the heart on the left is wild-type, and the right heart is from a mouse in which stable HIF-1 protein was expressed for two weeks. Notice the enlarged epicardial vessels, and dilation, of the HIF-1 heart.
Endothelial Responses to Cardiovascular Stress
Ongoing studies within our laboratory focus on a comprehensive examination of endothelial transcript-level responses to cardiovascular stress using relevant and well-defined mouse models of human pathophysiology.
Currently, our models include air pollution (diesel exhaust), atherosclerosis and diabetes. Previous studies in our laboratory of the response to lipopolysaccharide and environmental side-stream tobacco smoke revealed
changes in endothelial transcripts relating to host-defense and vasoregulation, respectively.
An authentic assessment of transcript-level changes is performed in vivo using mice which express green fluorescent protein exclusively within their endothelium (see figure on right).
Proteolytic digestion of cardiovascular tissues followedby FACS sorting allows isolation of these cells to high purity. Subsequent application of DNA microarray technology then allows
measurement of the transcript-level responses occurring within our models, using highly representative, long oligonucleotide microarrays.
Elucidating the Role of Endothelin-1 in the Heart
Endothelin (ET-1) is a hormone known primarily as a potent vasoconstrictor. ET receptor antagonists have been investigated for treatment of heart failure and are being used to treat pulmonary arterial hypertension.
We are interested in the role of endothelin-1 in the heart. Using Cre-LoxP technology, we have developed cardiac-specific knock-outs of the peptide and its receptors to elucidate the function of this signaling axis in cardiac tissue.
We have found that endogenously expressed ET-1 appears to protect cardiac myocytes as they age or are subjected to hemodynamic stress.
As demonstrated in the figure, mice with cardiac knock-out of ET-1 show cardiac dilation with age, decreased ventricular function by echocardiography,
and histological evidence of myocyte hypertrophy, heterogeneity and fibrosis, all typical for a dilated cardiomyopathy.
Ultrasound Targeted Microbubble Destruction (UTMD)
though protein and gene therapy strategies are promising, there has yet to be developed a highly efficient, reliable in vivo method for local delivery.
We have helped to develop a technique, termed ultrasound targeted microbubble destruction (UTMD), that allows for local delivery of moieties to specific regions in vivo.
Microbubbles, which are composed of a high molecular weight gas surrounded by a polymer, protein, or lipid shell, became popularized in the 1990’s as contrast agents for ultrasonic imaging of the cardiovascular system.
An ultrasonic signal of the correct strength can disrupt the bubbles, which allows for volumetric flow studies within vessels.
We have attached both plasmids and proteins to microbubbles, injected them into rats, and obtained efficient delivery to target organs by destroying the microbubbles with a properly guided ultrasonic signal.
Applications of this technology are vast, and a few of those currently being investigated include HIF-1 delivery to ischemic tissue, insulin delivery to pancreatic islet cells, and gene expression modification upon endothelial tissue.
Here, a microbubble is destroyed by an ultrasonic signal, thus releasing the attached moiety into the surrounding tissue (Physics Today, December 2005).
Human Genetics
Phenotypic differences between different human populations are often explained by genetic variation.
It is likely that susceptibility to cardiovascular disease, and to the illnesses, such as hypertension and diabetes, that contribute to heart disease, have meaningful genetic components.
We expect that the understanding of genetic variation in various populations will contribute to the mechanistic understanding of how cardiovascular disease develops, and why it affects different ethnic groups in distinct ways.
We are analyzing genomic information from various populations for shifts in allelic frequencies that will lead to a further comprehension of phenotypic variation and disease susceptibility.
We are also interested in any families that have a high frequency of cardiovascular illness or even more than a single case of unusual cardiac disease.
An authentic assessment of transcript-level changes is performed in vivo using mice which express green fluorescent protein exclusively within their endothelium (see figure on right). Proteolytic digestion of cardiovascular tissues followedby FACS sorting allows isolation of these cells to high purity. Subsequent application of DNA microarray technology then allows measurement of the transcript-level responses occurring within our models, using highly representative, long oligonucleotide microarrays.
Elucidating the Role of Endothelin-1 in the Heart
Endothelin (ET-1) is a hormone known primarily as a potent vasoconstrictor. ET receptor antagonists have been investigated for treatment of heart failure and are being used to treat pulmonary arterial hypertension.
We are interested in the role of endothelin-1 in the heart. Using Cre-LoxP technology, we have developed cardiac-specific knock-outs of the peptide and its receptors to elucidate the function of this signaling axis in cardiac tissue.
We have found that endogenously expressed ET-1 appears to protect cardiac myocytes as they age or are subjected to hemodynamic stress.
As demonstrated in the figure, mice with cardiac knock-out of ET-1 show cardiac dilation with age, decreased ventricular function by echocardiography,
and histological evidence of myocyte hypertrophy, heterogeneity and fibrosis, all typical for a dilated cardiomyopathy.
Ultrasound Targeted Microbubble Destruction (UTMD)
though protein and gene therapy strategies are promising, there has yet to be developed a highly efficient, reliable in vivo method for local delivery.
We have helped to develop a technique, termed ultrasound targeted microbubble destruction (UTMD), that allows for local delivery of moieties to specific regions in vivo.
Microbubbles, which are composed of a high molecular weight gas surrounded by a polymer, protein, or lipid shell, became popularized in the 1990’s as contrast agents for ultrasonic imaging of the cardiovascular system.
An ultrasonic signal of the correct strength can disrupt the bubbles, which allows for volumetric flow studies within vessels.
We have attached both plasmids and proteins to microbubbles, injected them into rats, and obtained efficient delivery to target organs by destroying the microbubbles with a properly guided ultrasonic signal.
Applications of this technology are vast, and a few of those currently being investigated include HIF-1 delivery to ischemic tissue, insulin delivery to pancreatic islet cells, and gene expression modification upon endothelial tissue.
Here, a microbubble is destroyed by an ultrasonic signal, thus releasing the attached moiety into the surrounding tissue (Physics Today, December 2005).
Human Genetics
Phenotypic differences between different human populations are often explained by genetic variation.
It is likely that susceptibility to cardiovascular disease, and to the illnesses, such as hypertension and diabetes, that contribute to heart disease, have meaningful genetic components.
We expect that the understanding of genetic variation in various populations will contribute to the mechanistic understanding of how cardiovascular disease develops, and why it affects different ethnic groups in distinct ways.
We are analyzing genomic information from various populations for shifts in allelic frequencies that will lead to a further comprehension of phenotypic variation and disease susceptibility.
We are also interested in any families that have a high frequency of cardiovascular illness or even more than a single case of unusual cardiac disease.
As demonstrated in the figure, mice with cardiac knock-out of ET-1 show cardiac dilation with age, decreased ventricular function by echocardiography, and histological evidence of myocyte hypertrophy, heterogeneity and fibrosis, all typical for a dilated cardiomyopathy.
Ultrasound Targeted Microbubble Destruction (UTMD)
though protein and gene therapy strategies are promising, there has yet to be developed a highly efficient, reliable in vivo method for local delivery.
We have helped to develop a technique, termed ultrasound targeted microbubble destruction (UTMD), that allows for local delivery of moieties to specific regions in vivo.
Microbubbles, which are composed of a high molecular weight gas surrounded by a polymer, protein, or lipid shell, became popularized in the 1990’s as contrast agents for ultrasonic imaging of the cardiovascular system.
An ultrasonic signal of the correct strength can disrupt the bubbles, which allows for volumetric flow studies within vessels.
We have attached both plasmids and proteins to microbubbles, injected them into rats, and obtained efficient delivery to target organs by destroying the microbubbles with a properly guided ultrasonic signal.
Applications of this technology are vast, and a few of those currently being investigated include HIF-1 delivery to ischemic tissue, insulin delivery to pancreatic islet cells, and gene expression modification upon endothelial tissue.
Here, a microbubble is destroyed by an ultrasonic signal, thus releasing the attached moiety into the surrounding tissue (Physics Today, December 2005).
Human Genetics
Phenotypic differences between different human populations are often explained by genetic variation.
It is likely that susceptibility to cardiovascular disease, and to the illnesses, such as hypertension and diabetes, that contribute to heart disease, have meaningful genetic components.
We expect that the understanding of genetic variation in various populations will contribute to the mechanistic understanding of how cardiovascular disease develops, and why it affects different ethnic groups in distinct ways.
We are analyzing genomic information from various populations for shifts in allelic frequencies that will lead to a further comprehension of phenotypic variation and disease susceptibility.
We are also interested in any families that have a high frequency of cardiovascular illness or even more than a single case of unusual cardiac disease.
Here, a microbubble is destroyed by an ultrasonic signal, thus releasing the attached moiety into the surrounding tissue (Physics Today, December 2005).
Human Genetics
Phenotypic differences between different human populations are often explained by genetic variation.
It is likely that susceptibility to cardiovascular disease, and to the illnesses, such as hypertension and diabetes, that contribute to heart disease, have meaningful genetic components.
We expect that the understanding of genetic variation in various populations will contribute to the mechanistic understanding of how cardiovascular disease develops, and why it affects different ethnic groups in distinct ways.
We are analyzing genomic information from various populations for shifts in allelic frequencies that will lead to a further comprehension of phenotypic variation and disease susceptibility.
We are also interested in any families that have a high frequency of cardiovascular illness or even more than a single case of unusual cardiac disease.