Marlene Rabinovitch, M.D. - Research Interests:
 |
Our research focuses on the regulation of genes associated with vascular
development and disease. We have shown that a novel smooth muscle cell
elastase plays a pivotal role in the pathobiology of cardiovascular
diseases including pulmonary hypertension, vein graft atherosclerosis,
transplant arteriopathy and rejection, coronary artery disease, restenosis,
myocardial ischemia and myocarditis. The mechanism is related to liberation
of growth factors and cytokines, activation of matrix metalloproteinases,
induction of tenascin-C, clustering of beta integrins and phosphorylation
of growth factor receptors. Inhibition of elastase prevents or reverses
the pathology in experimental animals. In vessels, this involves smooth
muscle cell apoptosis and caspase mediated degradation of the excess
extracellular matrix. We are now pursuing fundamental studies which
address the transcriptional regulation of elastase by AML1 and how
this relates to genetic mechanisms of disease, focusing on polymorphisms
in the serotonin transporter, mutations in a bone morphogenetic protein
receptor, and overexpression of a calcium binding protein, Mts1. These
studies use cultured cells, transgenic mice, gene arrays and gene therapy
and are aimed at developing new treatments.
In our studies related to regulation of cell motility, a key feature of vascular pathology, we identified the microtubule-associated protein LC-3 as pivotal in the efficiency of mRNA translation of genes including fibronectin and apolipoprotein D. We determined that LC3 is regulated by nitric oxide, and are currently investigating how this leads to its phosphorylation and binding to mRNA. In addition, we are relating LC-3 to the migration of other cell types including neural crest cells that regulate cardiac development. A new project with Dr. Kirkgaard (Professor of Microbiology) relates LC-3 to viral replication.
We have also cloned a novel chymase that regulates the enhanced production of angiotensin II, endothelin 1, collagen and transforming growth factor beta. Since the transgenic mouse that overexpresses this gene is hypertensive, and since the spontaneously hypertensive rat also produces excess chymase, we are investigating whether an increase in the synthesis of the human chymase enzyme is responsible for a refractory form of systemic hypertension.
A major program will be combined with that of Dr. Richard Bland in investigating the regulation, expression and function of genes that coordinate pulmonary alveolar and vascular development and how they are perturbed by prematurity and mechanical ventilation leading to chronic lung disease.
Ongoing research in the laboratory of Marlene Rabinovitch, M.D.
Richard D. Bland, M.D. - Research Interests:
Our research program focuses on lung growth and development, and the adverse impact of prolonged mechanical ventilation on the incompletely formed lung, which in very premature infants often leads to a life-threatening condition that was first described as bronchopulmonary dysplasia (Northway WH Jr et al,Stanford University, New Engl J Med 276: 357-368, 1967).
This form of neonatal chronic lung disease is the leading cause of long-term hospitalization and recurrent respiratory disorders seen in tiny infants who have been born at less than 28 weeks of gestation.Failed alveolar formation and excess, disordered lung elastin are prominent histological features of this disease, which in some ways resembles adult emphysema.
We study the effects of mechanical ventilation, with either air or 40% O2, on genes and proteins that regulate lung growth and development in newborn mice, whose alveoli and pulmonary capillaries form mainly after birth at term gestation. As elastin plays a crucial role in lung growth and development (elastin-null mice die soon after birth from cardiorespiratory failure related to defective alveolar and lung vascular formation), we are especially interested in studying the effects of prolonged mechanical ventilation (cyclic lung stretch) with O2-rich gas (which is often needed to sustain life of extremely premature infants) on genes that regulate elastin synthesis and assembly, which in turn can affect lung septation and angiogenesis. We currently study the effects of lengthy mechanical ventilation on lungs of mutant newborn mice that have defects in elastin assembly and associated abnormalities of lung structure. Because mechanical ventilation of the developing lung can induce the release of proteolytic enzymes that break down elastin, we recently began to study the effects of mechanical ventilation with O2-rich gas in a transgenic mouse that over-expresses elafin, a potent inhibitor of serine elastase activity. We think that these studies will pave the way for novel and effective strategies to treat or prevent neonatal chronic lung disease, and perhaps other respiratory disorders that exhibit similar pathological features in older children and adults.
Ongoing
research in the laboratory of Richard Bland, M.D.
Back to top 
