Research

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S. Alex  Mitsialis, PhD

S. Alex Mitsialis
Department:
Medicine Research
Division
Newborn Medicine Research
Hospital Title:
Associate Scientific Researcher
Academic Title:
Assistant Professor of Pediatrics, Harvard Medical School
Research Focus Area:
Molecular basis of lung injury and repair
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Research Overview

Molecular biology of oxygen-induced lung injury and protective/repair mechanisms. The pulmonary vasculature monitors and actively responds to changes in oxygen tension and associated changes in the intracellular levels of reactive oxygen intermediates. Such signals trigger gene expression cascades that play profound roles in vascular wall remodeling, vascular tone, and inflammatory processes, as exemplified by hypoxia-induced pulmonary hypertension. Dr. Mitsialis' laboratory has developed a number of animal models of experimental pulmonary hypertension based on genetically-modified mice and utilize them to understand the molecular basis of this disease. They are particularly interested in deciphering, at the molecular level, the pivotal signals that commit the vasculature towards a pathologic state, and how self-defense mechanisms, such as the action of cytoprotective genes or the activation of bone-marrow derived or lung-resident stem cells, can prevent or reverse the disease process.

Polymorphisms of cytoprotective genes and genomics of lung disease. The inducible isoform of Heme Oxygenase (HO-1) has been established as a crucial cytoprotective gene in a number of animal models. Recent clinical studies have associated genetic polymorphisms in transcriptional regulatory regions of the human HO-1 gene with protection from cardiovascular disease. Dr. Mitsialis' laboratory is characterizing the molecular mechanisms regulating human HO-1 basal expression and inducibility in response to diverse stress stimuli, by defining the impact of known polymorphisms on the composition and function of the HO-1 gene promoter transcriptional complexes. In parallel, they are screening a patient population for possible linkage of HO-1 regulatory polymorphisms, as well as genetic variants of other candidate genes, to the development of pulmonary diseases, in particular bronchopulmonary dysplasia (BPD), the most prevalent long-term complication of prematurity.

Respiratory epithelium function in airway disease. Ciliopathies underlie a wide spectrum of human genetic disorders, with both adult and developmental phenotypes. The prototype ciliopathy, Primary Ciliary Dyskinesia (PCD), is a genetically heterogeneous disorder. Patients exhibit varying degrees of clinical severity, manifested by development of bronchiectasis, inflammation, and development of features characteristic of chronic lung disease (COPD), the severity of lung disease being directly associated with the extent of loss of ciliary function in the affected epithelium. Dr. Mitsialis' laboratory has developed a novel animal model of PCD, based on the demonstration that ablation of a previously uncharacterized murine gene can result in severe defects in respiratory cilia structure and function. They are defining the molecular mechanisms through which this genetic lesion affects ciliary motility and lung epithelium integrity. In addition, they are establishing the framework for the development of tools to genetically screen human PCD cases of unknown etiology for putative mutations in this novel locus.

About S. Alex Mitsialis

Director, Animal Models of Lung Diseases, Division of Newborn Medicine

Education

1974 B.A., Biochemistry, Princeton University
1983 Ph.D., Microbiology, Columbia University
1986 Postdoctoral Fellowship in Developmental Biology, Harvard University

Memberships

American Heart Association, Basic Science Council
American Thoracic Society

Honors and Awards

CRC Freshman Chemistry Achievement Award; Tau Alpha Pi Honor Society; Princeton University Scholarship; National Science Foundation Traineeship; Scholar, Anglo-American-Hellenic Bureau of Education; University Fellow, College of Physicians & Surgeons, Columbia University; NIH and American Cancer Society Postdoctoral Fellowships; Medical Foundation Fellowship; NIH F.I.R.S.T. Award

Key Publications

  • Fredenburgh LE, Perrella MA, Mitsialis SA. The role of heme oxygenase-1 in pulmonary disease. Am J. Respir. Cell Mol. Biol. 2007;36:158-165.

  • Fernandez-Gonzalez A, Kourembanas S, Wyatt TA, Mitsialis SA. Mutation of murine adenylate kinase 7 underlies a primary ciliary dyskinesia phenotype. Am J. Respir. Cell Mol. Biol. 2009;40:305-313.

  • Aslam M, Baveja R, Liang OD, Fernandez-Gonzalez A, Lee C, Mitsialis SA, Kourembanas S. Bone marrow stromal cells attenuate lung injury in a murin
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