Mice lacking the EGF-receptor (EGF-R) exhibit delayed lung maturation, abnormal branching morphogenesis, and respiratory failure. The applicant has found that the epithelial cell lining of distal airways of new born EGF-R mice undergoes unscheduled programmed cell death (PCD), possibly as a result of defective signaling in pulmonary mesenchyme. Although the pulmonary mesenchyme has been shown to be essential for branching morphogenesis, the mechanism of this induction and the nature of the factors involved in these paracrine interactions are not known. The research in this application tests the hypothesis that mesenchymal signaling is important in branching morphogenesis.
The specific aims are as follows: 1) Describe the phenotypic characteristics of the lung in normal and EGF-R deficient mice throughout development and postnatally. 2) Determine which specific embryonic developmental events precede and may regulate augmented PCD in EGF-R null mice. 3) Determine whether EGF-R signaling is required in the epithelial or mesenchymal component of the developing lung. The critical intracellular and extracellular constituents of this signaling cascade, involving primitive mesenchyme and airway epithelium, will be tested using EGF-R null, and mutant EGF-R signaling-defective (waved-2) mice. Dr. Farrah Kheradmand is a postdoctoral research fellow at the University of California at San Francisco, has completed 12 months of clinical Pulmonary Medicine training and 36 months of research and authored or co-authored 7 manuscripts. The funding and other support provided by this award will allow Dr. Kheradmand to pursue investigations of epithelial-mesenchymal interactions in lung development. The proposed work will be performed at the Laboratory of Radiobiology, University of California San Francisco. The Department of Medicine is fully committed to the career development of Dr. Kheradmand. As such, Dr. Kheradmand will have at least 80% protected time for the duration of the award. UCSF offers an outstanding environment for academic advancement and training. Dr. Kheradmand's sponsor is Dr. Zena Werb; her co-sponsor is Dr. Dean Sheppard. Both are senior faculty members of UCSF and experts in the fields of cell and pulmonary biology, respectively. Also overseeing Dr. Kheradmand's career development and scientific progress are Advisory Committee members Drs. Michael Mafthay, Carol Basbaum, and Gerald Cunha, all senior faculty members of Division of Pulmonary and Department of Anatomy at UCSF.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-Y (M1))
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Baylor College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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Xu, Jie; Park, Pyong Woo; Kheradmand, Farrah et al. (2005) Endogenous attenuation of allergic lung inflammation by syndecan-1. J Immunol 174:5758-65
Kheradmand, Farrah; Kiss, Attila; Xu, Jie et al. (2002) A protease-activated pathway underlying Th cell type 2 activation and allergic lung disease. J Immunol 169:5904-11
Kheradmand, Farrah; Rishi, Kirtee; Corry, David B (2002) Environmental contributions to the allergic asthma epidemic. Environ Health Perspect 110 Suppl 4:553-6
Corry, David B; Rishi, Kirtee; Kanellis, John et al. (2002) Decreased allergic lung inflammatory cell egression and increased susceptibility to asphyxiation in MMP2-deficiency. Nat Immunol 3:347-53
Kheradmand, Farrah; Rishi, Kirtee; Werb, Zena (2002) Signaling through the EGF receptor controls lung morphogenesis in part by regulating MT1-MMP-mediated activation of gelatinase A/MMP2. J Cell Sci 115:839-48
Kheradmand, Farrah; Werb, Zena (2002) Shedding light on sheddases: role in growth and development. Bioessays 24:8-12
Werner, E; Kheradmand, F; Isberg, R R et al. (2001) Phagocytosis mediated by Yersinia invasin induces collagenase-1 expression in rabbit synovial fibroblasts through a proinflammatory cascade. J Cell Sci 114:3333-43
Kheradmand, F; Werner, E; Tremble, P et al. (1998) Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change. Science 280:898-902