Abstract

In this proposal, it is hypothesized that 1) movement of proSP-B, intermediates, and mature SP-B8 to the lamellar body is facilitated by organelle-specific compartmentalization of proSP-b processing, and 2) signals contained within the N- and C-terminal peptides flanking mature SP-B are important in trafficking SP-B to the lamellar body. Studies in Specific Aim 1 will clarify the steps in processing of human SP-B, and localize intermediates and cleavage products to subcellular organelles through the use of epitope-specific antibodies and organelle-specific markers, as well as pharmacologic agents that interfere with organelle transfer.
In Aim 2, a tagged SP-B cDNA using the FLAG-sequence will be developed to track recombinant SP-B through type 2 cells on a background of endogenous SP-B production. Key regions of the N- and C-terminal peptides of proSP-B will be altered to examine aberrant trafficking of the recombinant SP-B protein. These studies will be carried out in human fetal lung explants which in culture develop a large stable population of type 2 cells suitable for studying processing and trafficking of SP-B.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059959-05
Application #
6537368
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Berberich, Mary Anne
Project Start
1998-04-01
Project End
2002-12-18
Budget Start
2002-04-01
Budget End
2002-12-18
Support Year
5
Fiscal Year
2002
Total Cost
$127,750
Indirect Cost

  Institution

Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Sucre, Jennifer M S; Deutsch, Gail H; Jetter, Christopher S et al. (2018) A Shared Pattern of ?-Catenin Activation in Bronchopulmonary Dysplasia and Idiopathic Pulmonary Fibrosis. Am J Pathol 188:853-862
Jacob, Anjali; Morley, Michael; Hawkins, Finn et al. (2017) Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells. Cell Stem Cell 21:472-488.e10
Kook, Seunghyi; Wang, Ping; Young, Lisa R et al. (2016) Impaired Lysosomal Integral Membrane Protein 2-dependent Peroxiredoxin 6 Delivery to Lamellar Bodies Accounts for Altered Alveolar Phospholipid Content in Adaptor Protein-3-deficient pearl Mice. J Biol Chem 291:8414-27
Hawkins, Arie; Guttentag, Susan H; Deterding, Robin et al. (2015) A non-BRICHOS SFTPC mutant (SP-CI73T) linked to interstitial lung disease promotes a late block in macroautophagy disrupting cellular proteostasis and mitophagy. Am J Physiol Lung Cell Mol Physiol 308:L33-47
Cheong, Heesun; Wu, Junmin; Gonzales, Linda K et al. (2014) Analysis of a lung defect in autophagy-deficient mouse strains. Autophagy 10:45-56
Beers, Michael F; Zhao, Ming; Tomer, Yaniv et al. (2013) Disruption of N-linked glycosylation promotes proteasomal degradation of the human ATP-binding cassette transporter ABCA3. Am J Physiol Lung Cell Mol Physiol 305:L970-80
Taponen, Saija; Huusko, Johanna M; Petäjä-Repo, Ulla E et al. (2013) Allele-specific N-glycosylation delays human surfactant protein B secretion in vitro and associates with decreased protein levels in vivo. Pediatr Res 74:646-51
Mei, Junjie; Liu, Yuhong; Dai, Ning et al. (2012) Cxcr2 and Cxcl5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice. J Clin Invest 122:974-86
Mantegazza, Adriana R; Guttentag, Susan H; El-Benna, Jamel et al. (2012) Adaptor protein-3 in dendritic cells facilitates phagosomal toll-like receptor signaling and antigen presentation to CD4(+) T cells. Immunity 36:782-94
Beers, Michael F; Hawkins, Arie; Maguire, Jean Ann et al. (2011) A nonaggregating surfactant protein C mutant is misdirected to early endosomes and disrupts phospholipid recycling. Traffic 12:1196-210

Showing the most recent 10 out of 19 publications