Jacobs School of Medicine & Biomedical Sciences
Apoptosis and cell death; Cell growth, differentiation and development; Metabolism; Molecular and Cellular Biology; Molecular Basis of Disease; Protein Folding; Protein Function and Structure; Pulmonary; RNA; Stem Cells
The endoplasmic reticulum and the mitochondria are parts of a proteostasis network that undergoes age-related changes. The focus of my research has been to understand the adaptive and non-adaptive age-dependent reprogramming of cellular homeostasis in the lungs of smokers, with a focus on mitochondrial and endoplasmic reticulum age–related stress responses in local progenitor cells.
My laboratory is using exposure to cigarette smoke (CS) and to nicotine as model systems for environmentally induced physiological stressors in exposed cells, animals and humans.
We identified the first known mitochondria-encoded small non-coding RNA, mito-ncR-805, that mediates retrograde communication between the mitochondrial and nuclear genomes. During stress, mito-ncR-805 exits the mitochondria, and enters the nucleus, where it maintains the expression of nuclear-encoded mitochondrial genes, and by doing so preserves mitochondrial bioenergetics, and orchestrates adaptation of mitochondrial function to stressful conditions. Currently, we are working to understand the cell type specificity and the molecular mechanisms of the release of mito-ncR-805 from the mitochondria, the mechanism of its entrance into the nucleus, as well as the mechanism of its nuclear function, and the possibility to develop mito-ncR-805 into therapeutics for diseases that have a mitochondrial malfunction component as a leading factor in their pathogenesis.
We delineated the mechanisms of CS-effects on protein folding and identified a protein disulfide isomerase (PDI) as the first known ER target of cigarette smoke induced oxidation. PDI is one of the most abundant redox-sensitive ER resident proteins, and it plays a central role in disulfide bond formation, and redox homeostasis. CS-induced posttranslational PDI oxidation result in the induction of ER Stress Response (ERSR) in vitro and in vivo. Animals deficient in ERSR are fully protected from CS-associated fibrosis, and partially protected from inflammation and emphysema. Our current research aims to delineate redox signaling function of post-transnationally oxidized PDI, and establish which specific components of ERSR are involved and when they should be modulated by therapeutic approaches.
Our technical approach has been multidisciplinary including protein chemistry, cell and
molecular biology, advanced microscopy, genetic engineering, and animal models of disease.