Maria I. Ramirez, Ph.D.

Faculty and Fellows

Maria I. Ramirez, Ph.D.

Associate Professor of Medicine,

Associate Professor Pathology and Laboratory Medicine

Undergraduate: University of Buenos Aires, Argentina

Graduate PhD Program: University of Buenos Aires, Argentina School of Sciences.Department of Organic Chemistry
Post-doctoral Training: University of Massachusetts Medical Center

Department of Biochemistry and Molecular Biology.

Boston University School of Medicine, Department of Medicine, Pulmonary Center.

Parker B. Francis Fellowship.

Special Interests:

RESEARCH:

Epigenetic mechanisms of lung gene regulation in lung development and disease
Alveolar epithelial type I cell morphogenesis
We study: the specification of the endoderm to become lung epithelium, the differentiation of distal lung epithelium into alveolar type I cells perinatally and epithelial gene regulation in idiopathic pulmonary fibrosis.

Molecular mechanisms of lung cell differentiation: Role of epigenetic gene regulation.

During post gastrulation of the mouse embryo, the multipotent ventral foregut gives rise to the thyroid, lung, liver, and pancreas. A combination of local factors produced by the foregut and secreted molecules from neighboring organs, such as the heart establish different cell fates along the foregut endoderm. Foregut cells respond to these signals by initiating organ specific developmental programs. We are interested in identifying the molecules involved in acquisition of lung cell identity and understanding how the lung developmental program differs form that of other endodermal-derived organs. This is a critical step towards the development of new strategies of lung tissue repair. Especially, it is important to direct multipotent embryonic stem cells towards a lung epithelial fate. In a global analysis of gene expression of mouse foregut tissue we have identified significant changes in expression of genes associated with chromatin remodeling and DNA methylation coincident with formation of the lung primordium (Millien et al 2008). We are currently investigating the role of these epigenetic mechanisms in activation or silencing of gene expression during initiation of lung development and in diseases, such as pulmonary fibrosis.

Development of alveolar epithelial type I cells.

The extensive distal lung gas-exchange surface that supports respiration at birth forms in the last 4-5 days of gestation in mice. Formation of distal alveolar sacs requires differentiation of epithelial type I and type II cells and thinning of the mesenchyme. Expression of cell specific genes, the extended and attenuated cell shape, and the location within the distal lung are the key features used to define a lung alveolar type I cell. T1α is a type I cell differentiation marker gene highly expressed in the apical cell membrane. Mice lacking T1α are unable to breathe at birth, have deficient alveolar sac formation and type I cell differentiation (Ramirez et al, 2003). Using mice lacking T1α and other genetically modified mice generated in our laboratory, we are studying alveolar sac formation and type I cell differentiation at late gestation (Millien et al 2006). We are particularly interested in studying the molecular mechanisms that underlie flattening of lung alveolar epithelial type I cells during development using in vitro and in vivo models of normal and altered lung epithelial morphogenesis.

Dr. Ramirez is an NIH-funded Principal Investigator and a member of the Epithelial Group, and the Developmental Biology Group at the Pulmonary Center.

Selected Publications:

  1. Millien, G., Beane, J., Lenburg, M., Tsao, P., Lu, J., Spira, A., Ramirez, M.I. (2008) Characterization of the mid-foregut transcriptome identifies genes regulated during lung bud induction. Gene Expression Patterns 8(2):124-139.
  2. Pogach M.S., Cao, Y., Millien, G., Ramirez, M.I., Williams, M.C. (2007) Key developmental regulators change during hyperoxia-induced injury and recovery in adult mouse lung. J. Cell. Biochem. 100(6):1415-29.
  3. Kathuria, H., Cao, Y.X., Hinds, M.I., Ramirez, M.I. , Williams, M.C. (2007) The ETS protein ERM regulates caveolin-1 transcription in mouse lung epithelial, but not endothelial cell lines. J Cell Biochem. 102(1):13-27.
  4. Millien, G., Spira, A., Hinds, A., Wang, J., Williams, M.C., Ramirez, M.I. (2006) Alterations in gene expression in T1alpha null lung: a model of deficient alveolar sac development. BMC Dev. Biol. 6(1):35.
  5. Kathuria, H., Cao, Y.X., Ramirez, M. I. , Williams, M.C. (2004) Transcription of the caveolin-1 gene is differentially regulated in lung type I epithelial and endothelial cell lines: A role for ETS proteins in epithelial cell expression J Biol Chem . 279:30028-36
  6. Wongtrakool, C., Malpel, S., Gorestein, J., Sedita, J., Ramirez, M. I ., Underhill, M., Cardoso, W. C. (2003) Downregulation of retinoic acid receptor a signaling is required for sacculation and type I cell formation in the developing lung. J. Biol. Chem . 278:46911-46918.
  7. Cao, Y. X., Ramirez, M. I ., Williams, M. C. (2003) Enhanced bindig of Sp1/Sp3 transcription factors mediates the hyperoxia-induced increased expression of the lung type I cell gene T1α. J. Cell Biol. 89: 887-901.
  8. *Schacht, V., * Ramirez, M .I. , Hong, Y., Hirakawa, S., Feng, D., Harvey , N., Williams, M., Dvorak, A. M., Dvorak, H. F., Oliver, G., Detmar, M. (2003) T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J. 22: 3546-3556 (*equal contribution).
  9. Ramirez, M. I., Millien, G., Hinds, A., Cao, Y. X., Seldin, D., Williams, M. C. (2003) T1α, a lung type I cell differentiation gene, is required for normal lung cell proliferation and alveolus formation at birth. Dev. Biol . 256, 61-72.
  10. Ramirez, M. I., Chung, U-I., and Williams, M. C. (2000) Aquaporin-5 expression, but not other peripheral lung marker genes, is reduced in PTH/PTHrP receptor null mutant fetal mice. Am. J. Respir. Cell Mol. Biol. 22 :367-372.
  11. Ramirez, M. I., Pollack, L., Millien, G., Cao, Y. X., Hinds, A., Williams, M. C. (2002) The α-isoform of caveolin-1 is a marker of vasculogenesis in early lung development. J. Histochem. Cytochem 50 :33-42.
  12. Ramirez, M. I., Cao, Y. X., and Williams, M. C. (1999) 1.3 kilobases of the lung type I cell T1α gene promoter mimics endogenous gene expression patterns during development but lacks sequences to enhance expression in perinatal and adult lung. Dev. Dyn . 215 :319-331.
  13. Ramirez, M. I., Rishi, A. K., Cao, Y. X., and Williams, M. C. (1997) TGT3, thyroid transcription factor I, and Sp1 elements regulate transcriptional activity of the 1.3-kilobase pair promoter of T1α, a lung alveolar type I cell gene. J. Biol. Chem . 272 :26285-26294.

Selected Reprints:

  1. 1.3 kilobases of the lung type I cell T1α gene promoter mimics endogenous gene expression patterns during development but lacks sequences to enhance expression in perinatal and adult lung.
  2. T1α, a lung type I cell differentiation gene, is required for normal lung cell proliferation and alveolus formation at birth.
  3. TGT3, thyroid transcription factor I, and Sp1 elements regulate transcriptional activity of the 1.3-kilobase pair promoter of T1α, a lung alveolar type I cell gene.

Links:

Developmental Biology

Epithelial Biology

Ramirez Lab

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Primary teaching affiliate
of BU School of Medicine