Bio

Clinical Focus


  • Pulmonary Disease

Honors & Awards


  • Mentored Clinical Scientist Research Career Development Award (K08), NIH (2008-2013)
  • Fellowship in Pulmonary Research, Parker B. Francis Foundation (2006-2009)
  • Pulmonary Fellowship Award, GlaxoSmithKline (2002-2003)
  • Robert Dawson Evans Fellow Excellence in Teaching Award, Boston University School of Medicine, Department of Internal Medicine (2000)
  • House Officer Research Award, University of Michigan Hospitals, Department of Internal Medicine (1998)
  • Worth F. Bloom M25 Prize, Tufts University School of Medicine (1995)

Professional Education


  • Medical Education:Tufts University (1995) MA
  • Internship:University of Michigan Medical Center (1996) MI
  • Residency:University of Michigan Medical Center (1998) MI
  • Board Certification: Pulmonary Disease, American Board of Internal Medicine (2001)
  • Fellowship:Boston University School of Medicine (2002) MA
  • BA, Amherst College, Psychology (1991)
  • MD, MPH, Tufts University School of Medicine, Medicine, Public Health (1995)

Research & Scholarship

Current Research and Scholarly Interests


My lab is interested in understanding how alveolar epithelial type (AT) 1 and AT 2 cells are generated during lung development and replaced in adult life during aging and following injury. We use mouse genetic tools to specifically mark and fate-map AT 1 and AT 2 cells, in order to understand their differentiative potential and the lineage hierarchies that operate during alveolar epithelial turnover. By genetically deleting or mis-expressing transcription factors and other genes in AT 1 and AT 2 cells, we are also seeking to elucidate the specific role each gene plays in these cells and indirectly in the lung overall. We are interested not only in the role for AT 1 and AT 2 cells in health, but in exploring how their depletion or dysregulation may contribute to specific diseases, such as adenocarcinoma, emphysema, bronchopulmonary dysplasia, and fibrotic diseases of the lung.

Teaching

2013-14 Courses


Graduate and Fellowship Programs


Publications

Journal Articles


  • Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature Desai, T. J., Brownfield, D. G., Krasnow, M. A. 2014; 507 (7491): 190-194

    Abstract

    Alveoli are gas-exchange sacs lined by squamous alveolar type (AT) 1 cells and cuboidal, surfactant-secreting AT2 cells. Classical studies suggested that AT1 arise from AT2 cells, but recent studies propose other sources. Here we use molecular markers, lineage tracing and clonal analysis to map alveolar progenitors throughout the mouse lifespan. We show that, during development, AT1 and AT2 cells arise directly from a bipotent progenitor, whereas after birth new AT1 cells derive from rare, self-renewing, long-lived, mature AT2 cells that produce slowly expanding clonal foci of alveolar renewal. This stem-cell function is broadly activated by AT1 injury, and AT2 self-renewal is selectively induced by EGFR (epidermal growth factor receptor) ligands in vitro and oncogenic Kras(G12D) in vivo, efficiently generating multifocal, clonal adenomas. Thus, there is a switch after birth, when AT2 cells function as stem cells that contribute to alveolar renewal, repair and cancer. We propose that local signals regulate AT2 stem-cell activity: a signal transduced by EGFR-KRAS controls self-renewal and is hijacked during oncogenesis, whereas another signal controls reprogramming to AT1 fate.

    View details for DOI 10.1038/nature12930

    View details for PubMedID 24499815

  • Stem cells: Differentiated cells in a back-up role. Nature Desai, T. J., Krasnow, M. A. 2013; 503 (7475): 204-205

    View details for DOI 10.1038/nature12706

    View details for PubMedID 24196710

  • Smooth muscle protein 22 alpha-mediated patchy deletion of Bmpr1a impairs cardiac contractility but protects against pulmonary vascular remodeling CIRCULATION RESEARCH El-Bizri, N., Wang, L., Merklinger, S. L., Guignabert, C., Desai, T., Urashima, T., Sheikh, A. Y., Knutsen, R. H., Mecham, R. P., Mishina, Y., Rabinovitch, M. 2008; 102 (3): 380-388

    Abstract

    Vascular expression of bone morphogenetic type IA receptor (Bmpr1a) is reduced in lungs of patients with pulmonary arterial hypertension, but the significance of this observation is poorly understood. To elucidate the role of Bmpr1a in the vascular pathology of pulmonary arterial hypertension and associated right ventricular (RV) dysfunction, we deleted Bmpr1a in vascular smooth muscle cells and in cardiac myocytes in mice using the SM22alpha;TRE-Cre/LoxP;R26R system. The LacZ distribution reflected patchy deletion of Bmpr1a in the lung vessels, aorta, and heart of SM22alpha;TRE-Cre;R26R;Bmpr1a(flox/+) and flox/flox mutants. This reduction in BMPR-IA expression was confirmed by Western immunoblot and immunohistochemistry in the flox/flox group. This did not affect pulmonary vasoreactivity to acute hypoxia (10% O2) or the increase in RV systolic pressure and RV hypertrophy following 3 weeks in chronic hypoxia. However, both SM22alpha;TRE-Cre;R26R;Bmpr1a(flox/+) and flox/flox mutant mice had fewer muscularized distal pulmonary arteries and attenuated loss of peripheral pulmonary arteries compared with age-matched control littermates in hypoxia. When Bmpr1a expression was reduced by short interference RNA in cultured pulmonary arterial smooth muscle cells, serum-induced proliferation was attenuated explaining decreased hypoxia-mediated muscularization of distal vessels. When Bmpr1a was reduced in cultured microvascular pericytes by short interference RNA, resistance to apoptosis was observed and this could account for protection against hypoxia-mediated vessel loss. The similar elevation in RV systolic pressure and RV hypertrophy, despite the attenuated remodeling with chronic hypoxia in the flox/flox mutants versus controls, was not a function of elevated left ventricular end diastolic pressure but was associated with increased periadventitial deposition of elastin and collagen, potentially influencing vascular stiffness.

    View details for DOI 10.1161/CIRCRESAHA.107.161059

    View details for Web of Science ID 000253194600018

    View details for PubMedID 18079409

  • In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses J Virol Grimm D, Lee JS, Wang L, Desai T, Akache B, Storm TA, Kay MA 2008; 82 (12): 5887-5911
  • Inhibition of Tgf beta signaling by endogenous retinoic acid is essential for primary lung bud induction DEVELOPMENT Chen, F., Desai, T. J., Qian, J., Niederreither, K., Lu, J., Cardoso, W. V. 2007; 134 (16): 2969-2979

    Abstract

    Disruption of retinoic acid (RA) signaling during early development results in severe respiratory tract abnormalities, including lung agenesis. Previous studies suggest that this might result from failure to selectively induce fibroblast growth factor 10 (Fgf10) in the prospective lung region of the foregut. Little is known about the RA-dependent pathways present in the foregut that may be crucial for lung formation. By performing global gene expression analysis of RA-deficient foreguts from a genetic [retinaldehyde dehydrogenase 2 (Raldh2)-null] and a pharmacological (BMS493-treated) mouse model, we found upregulation of a large number of Tgfbeta targets. Increased Smad2 phosphorylation further suggested that Tgfbeta signaling was hyperactive in these foreguts when lung agenesis was observed. RA rescue of the lung phenotype was associated with low levels of Smad2 phosphorylation and downregulation of Tgfbeta targets in Raldh2-null foreguts. Interestingly, the lung defect that resulted from RA-deficiency could be reproduced in RA-sufficient foreguts by hyperactivating Tgfbeta signaling with exogenous TGF beta 1. Preventing activation of endogenous Tgfbeta signaling with a pan-specific TGFbeta-blocking antibody allowed bud formation and gene expression in the lung field of both Raldh2-null and BMS493-treated foreguts. Our data support a novel mechanism of RA-Tgfbeta-Fgf10 interactions in the developing foregut, in which endogenous RA controls Tgfbeta activity in the prospective lung field to allow local expression of Fgf10 and induction of lung buds.

    View details for DOI 10.1242/dev.006221

    View details for Web of Science ID 000248385000009

    View details for PubMedID 17634193

  • Distinct roles for retinoic acid receptors alpha and beta in early lung morphogenesis DEVELOPMENTAL BIOLOGY Desai, T. J., Chen, F., Lu, J. M., Qian, J., Niederreither, K., Dolle, P., Chambon, P., Cardoso, W. V. 2006; 291 (1): 12-24

    Abstract

    Retinoic acid (RA) signaling is required for normal development of multiple organs. However, little is known about how RA influences the initial stages of lung development. Here, we used a combination of genetic, pharmacological and explant culture approaches to address this issue, and to investigate how signaling by different RA receptors (RAR) mediates the RA effects. We analyzed initiation of lung development in retinaldehyde dehydrogenase-2 (Raldh2) null mice, a model in which RA signaling is absent from the foregut from its earliest developmental stages. We provide evidence that RA is dispensable for specification of lung cell fate in the endoderm. By using synthetic retinoids to selectively activate RAR alpha or beta signaling in this model, we demonstrate novel and unique functions of these receptors in the early lung. We show that activation of RAR beta, but not alpha, induces expression of the fibroblast growth factor Fgf10 and bud morphogenesis in the lung field. Similar analysis of wild type foregut shows that endogenous RAR alpha activity is required to maintain overall RA signaling, and to refine the RAR beta effects in the lung field. Our data support the idea that balanced activation of RAR alpha and beta is critical for proper lung bud initiation and endodermal differentiation.

    View details for DOI 10.1016/j.ydbio.2005.10.045

    View details for Web of Science ID 000236128300002

    View details for PubMedID 16427040

  • Retinoic acid selectively regulates Fgf10 expression and maintains cell identity in the prospective lung field of the developing foregut DEVELOPMENTAL BIOLOGY Desai, T. J., Malpel, S., Flentke, G. R., Smith, S. M., Cardoso, W. V. 2004; 273 (2): 402-415

    Abstract

    Although respiratory tract defects that result from disruption of retinoic acid (RA) signaling have been widely reported, the mechanism by which endogenous RA regulates early lung morphogenesis is unknown. Here, we provide novel evidence that a major role for RA is to selectively maintain mesodermal proliferation and induce fibroblast growth factor 10 (Fgf10) expression in the foregut region where the lung forms. By using a pan-RAR antagonist (BMS493) in foregut explant cultures, we show that bud initiation is selectively blocked in the prospective respiratory region by failure to induce Fgf10 in the corresponding mesoderm. The RA regulation of Fgf10 expression occurs only in this region, within a defined developmental window, and is not seen in other foregut derivatives such as thyroid and pancreas where Fgf10 is also required for normal development. Furthermore, we show that RA activity is essential in the lung field to maintain lung cell identity in the endoderm; RAR antagonism disrupts expression of thyroid transcription factor 1 (Ttf1), an early marker of the respiratory region in the endoderm, and surfactant protein C (Sp-C) mRNAs. Our observations in mouse foregut cultures are corroborated by data from an in vivo model of vitamin A deficiency in rats. Our study supports RA as an essential regulator of gene expression and cellular activities during primary bud formation.

    View details for DOI 10.1016/j.ydbio.2004.04.039

    View details for Web of Science ID 000223681000018

    View details for PubMedID 15328022

  • COPD: Clinical Manifestations, Diagnosis, and Treatment Baum's Textbook of Pulmonary Diseases (Eds: James D. Crapo, Jeffrey Glassroth, Joel Karlinsky, and Talmadge E. King Jr.) Desai TJ, Karlinsky, JB 2004; 7th ed
  • Growth factors in lung development and disease: friends or foe? Respiratory research Desai, T. J., Cardoso, W. V. 2002; 3: 2-?

    Abstract

    Growth factors mediate tissue interactions and regulate a variety of cellular functions that are critical for normal lung development and homeostasis. Besides their involvement in lung pattern formation, growth and cell differentiation during organogenesis, these factors have been also implicated in modulating injury-repair responses of the adult lung. Altered expression of growth factors, such as transforming growth factor beta1, vascular endothelial growth factor and epidermal growth factor, and/or their receptors, has been found in a number of pathological lung conditions. In this paper, we discuss the dual role of these molecules in mediating beneficial feedback responses or responses that can further damage lung integrity; we shall also discuss the basis for their prospective use as therapeutic agents.

    View details for PubMedID 11806837

  • Participation of urokinase-type plasminogen activator receptor in the clearance of fibrin from the lung AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Hattori, N., Sisson, T. H., Xu, Y., Desai, T. J., Simon, R. H. 1999; 277 (3): L573-L579

    Abstract

    In vitro studies have demonstrated that the binding of urokinase-type plasminogen activator (uPA) to its cell surface receptor (uPAR) greatly accelerates plasminogen activation. However, the role of uPAR in clearing abnormal fibrin deposits from the lung is uncertain. Knowing that uPA binding to uPAR is species specific, we used adenoviral vectors to transfer human or murine uPA genes into human or mouse epithelial cells in vitro and to mouse lungs in vivo. By measuring degradation of fluorescein-labeled fibrin, we found that uPA lysed fibrin matrices more efficiently when expressed in cells of the same species. A monoclonal antibody that blocks the binding of human uPA to human uPAR suppressed fibrin degradation by human cells expressing human uPA but not murine uPA. Importantly, 3 days after intratracheal delivery of the vectors, mice receiving murine uPA transgenes degraded fibrin matrices formed within their air spaces more efficiently than animals transduced with human uPA genes. These results show that uPA bound to uPAR increases the efficiency of fibrinolysis on epithelial cell surfaces in a biologically relevant fashion.

    View details for Web of Science ID 000082425100017

    View details for PubMedID 10484465

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