The respiratory tract, like other mucosal surfaces, is protected by a multifaceted immune system from exposure to pathogenic microorganisms, environmental particulates, and allergens. Remarkably, the normal distal respiratory epithelial surface is free of chronic inflammation, a situation that optimizes gas exchange across the alveolar membrane. The collectin proteins (collagen-like lectins) are components of the multifaceted innate response in the blood and at most mucosal surfaces of the body. Two collectins, surfactant protein A (SP-A) and surfactant protein D (SP-D), are secreted by respiratory epithelial cells into the lining fluids of the respiratory tract, in good position to modulate the immune response. In this proposal, we will focus on the role of SP-D in host defense against influenza virus and address a possibly novel role for SP-D in modulating the acquired immune response to viral infection. We will also test the hypothesis that variations in collectin quaternary structure, specifically variability in self-association of SP-D trimers into higher-order multimers, modulates the function of SP-D in defense against influenza. We further hypothesize that substitution of a threonine for a methionine at position 11 in human SP-D due to a common SNP is a genetic determinant of SP-D multimer formation. Our study design is based on the truism that structure begets function. We will first characterize the biochemical basis for SP-D multimer formation and the altered quaternary structures caused by the Met^11Thr-encoding SNP (aim 1). We will then study the role of SP-D, and its variant haplotypes, in antigen presentation and the acquired cellular response to influenza in vitro and in vivo (aims 2 and 3).

Public Health Relevance

This proposal studies a surfactant-associated protein (SP-D) involved in protecting mucosal surfaces from infection and inflammation. We will study how the structure of the protein is related to function and how common variations in the human genome affect the immuno-modulatory functions of SP-D. The results may relate to the development of new therapies including new vaccination strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL024075-34
Application #
8603257
Study Section
Special Emphasis Panel (ZHL1-PPG-S)
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
34
Fiscal Year
2014
Total Cost
$268,298
Indirect Cost
$94,333
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Barrette, Anne Marie; Roberts, Jessica K; Chapin, Cheryl et al. (2016) Antiinflammatory Effects of Budesonide in Human Fetal Lung. Am J Respir Cell Mol Biol 55:623-632
Vanderbilt, Jeff N; Gonzalez, Robert F; Allen, Lennell et al. (2015) High-efficiency type II cell-enhanced green fluorescent protein expression facilitates cellular identification, tracking, and isolation. Am J Respir Cell Mol Biol 53:14-21
Gonzales, Linda W; Gonzalez, Robert; Barrette, Anne Marie et al. (2015) Expression of Carcinoembryonic Cell Adhesion Molecule 6 and Alveolar Epithelial Cell Markers in Lungs of Human Infants with Chronic Lung Disease. J Histochem Cytochem 63:908-21
Danhaive, Olivier; Chapin, Cheryl; Horneman, Hart et al. (2015) Surface film formation in vitro by infant and therapeutic surfactants: role of surfactant protein B. Pediatr Res 77:340-6
Raymond, Wilfred W; Xu, Xiang; Nimishakavi, Shilpa et al. (2015) Regulation of hepatocyte growth factor in mice with pneumonia by peptidases and trans-alveolar flux. PLoS One 10:e0125797
LaFemina, Michael J; Sutherland, Katherine M; Bentley, Trevor et al. (2014) Claudin-18 deficiency results in alveolar barrier dysfunction and impaired alveologenesis in mice. Am J Respir Cell Mol Biol 51:550-8
Gonzalez, Robert F; Dobbs, Leland G (2013) Isolation and culture of alveolar epithelial Type I and Type II cells from rat lungs. Methods Mol Biol 945:145-59
Chapin, Cheryl; Bailey, Nicole A; Gonzales, Linda W et al. (2012) Distribution and surfactant association of carcinoembryonic cell adhesion molecule 6 in human lung. Am J Physiol Lung Cell Mol Physiol 302:L216-25
Heine, Vivi M; Griveau, Amelie; Chapin, Cheryl et al. (2011) A small-molecule smoothened agonist prevents glucocorticoid-induced neonatal cerebellar injury. Sci Transl Med 3:105ra104
Gonzalez, Robert F; Allen, Lennell; Gonzales, Linda et al. (2010) HTII-280, a biomarker specific to the apical plasma membrane of human lung alveolar type II cells. J Histochem Cytochem 58:891-901

Showing the most recent 10 out of 176 publications