The Host Defense Group of the Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences, headed by Michael B. Fessler, MD now enters its second year at the NIEHS since inception. We have increased our staffing to 4 active laboratory members, and expect another 2 postdocs to join the group within the next 2 months. Moreover, we have submitted a project on a competitive intramural Direcors Challenge Program that, if awarded, will provide our Group with resources to hire 2 additional fellows and to extend our macrophage innate immunity work into atherosclerosis applications. Accomplishments include an original manuscript currently under revision for Journal of Immunology that defines novel roles for the nuclear receptor Liver X Receptor in modulation of pulmonary innate immunity, a meeting abstract on similar material in press to be published in the Proceedings of the American Thoracic Society, 2 middle-author collaborative publications (J Immunol, J All Clin Immunol), and an invited peer-reviewed review article on Liver X Receptor under review for Current Signal Transduction Therapy. Additional accomplishments include a 2008 FARE abstract award for Research Fellow Suraj Dhungana, and a successful competitive application to the NIH Office of Rare Diseases to secure supportive funding for an NIEHS-based symposium on lipid raft biology to be chaired by the PI, that will also correspond with his hosting of a Distinguished Lectureship speaker world-renowned in field of raft biology, Kai Simons. Three talks were delivered by the PI at international, national, and regional meetings, respectively, during the last year. In addition, substantial data has been collected on 5 active research projects in the laboratory: 1) characterization of apoplipoprotein A-I as a novel stimulus of innate immunity; 2) characterization of apolipoproteins A-I and E as novel endogenous regulators of pulmonary innate immunity in a murine model of inhaled LPS; 3) proteomic discovery of novel signaling proteins recruited to macrophage lipid rafts in response to LPS (this latter work has led to several targets which are currently undergoing functional validation for a role in the LPS signaling cascade with the use of RNAi in macrophages); and 4) identification of a modulatory role of high-cholesterol diet upon pulmonary innate immunity in a murine model of inhaled LPS. In addition, several mouse strains deficient in selected regulators of cholesterol trafficking have been procured and either rederived and bred, or are currently undergoing rederivation with an eye towards using them as tools to clarify a role for these regulatory targets in pulmonary innate immunity in vivo. Finally, we believe we have identified a novel TLR4 agonist of viral origin that we plan to characterize and validate further pending the hire of a postdoctoral fellow. Presently, 2 new original manuscripts are under preparation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES102005-02
Application #
7594021
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2007
Total Cost
$1,342,429
Indirect Cost
City
State
Country
United States
Zip Code
Kamal, Abu Hena M; Fessler, Michael B; Chowdhury, Saiful M (2018) Comparative and network-based proteomic analysis of low dose ethanol- and lipopolysaccharide-induced macrophages. PLoS One 13:e0193104
Fessler, Michael B (2018) The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease. Pharmacol Ther 181:1-12
Fessler, Michael B (2017) A New Frontier in Immunometabolism. Cholesterol in Lung Health and Disease. Ann Am Thorac Soc 14:S399-S405
Fessler, Michael B (2017) CO2 as a Potential Obesogen: A Gas That Will Stick to Your Ribs. Am J Respir Cell Mol Biol 57:499-500
Sakamachi, Yosuke; Morioka, Sho; Mihaly, September R et al. (2017) TAK1 regulates resident macrophages by protecting lysosomal integrity. Cell Death Dis 8:e2598
Suratt, Benjamin T; Ubags, Niki D J; Rastogi, Deepa et al. (2017) An Official American Thoracic Society Workshop Report: Obesity and Metabolism. An Emerging Frontier in Lung Health and Disease. Ann Am Thorac Soc 14:1050-1059
Fessler, Michael B; Carnes, Megan U; Salo, Päivi M et al. (2017) House Dust Endotoxin and Peripheral Leukocyte Counts: Results from Two Large Epidemiologic Studies. Environ Health Perspect 125:057010
Azzam, Kathleen M; Madenspacher, Jennifer H; Cain, Derek W et al. (2017) Irgm1 coordinately regulates autoimmunity and host defense at select mucosal surfaces. JCI Insight 2:
Lowe, Julie M; Nguyen, Thuy-Ai; Grimm, Sara A et al. (2017) The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression. Cell Death Differ 24:181-191
Madenspacher, Jennifer H; Fessler, Michael B (2016) A Non-invasive and Technically Non-intensive Method for Induction and Phenotyping of Experimental Bacterial Pneumonia in Mice. J Vis Exp :

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