This is a competitive revision to the active parent application RO1 DE15989: """"""""Role of Obesity in Infection"""""""" in response to Notice Number (NOT-OD-09-058) and Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. Obesity affects over 1 billion adults and 17.6 million children under 5 years of age. Obesity is known to result in a dysregulation of the innate immune response to infection. While the molecular mechanism that underlies this immune/inflammatory-metabolic linkage is not well understood recent studies have linked obesity to periodontal disease, a common infectious disease associated with the bacterium Porphyromonas gingivalis (P.g), and characterized by inflammation and destruction of periodontal tissues. Our own data shows that feeding mice a high fat diet induces defective proinflammatory cytokine response to P.g infection. In this two-year revision, we will extend the scope of the parent aims P- Aim 2b and P-Aim 2c and hire 2 more graduate students to accelerate the tempo of discovery . Specifically, we will identify a set of genes that are essential in the response to infection in mouse bone marrow macrophage (BMM) cells and will design modifications of these genes that will bring the response to infection of obese (OB) cells close to the response of lean (LN) cells. The response to infection will be quantified by the expression levels of five genes TNF, IL-6, iNOS, IL-10, and IL-1. According to the parent aim P-Aim 2b, we will focus on a specific TLR2 signaling pathway, which is thought to play a central role in the response to bacterial infection. The focus of the metabolic study will be on the effect of FFA, according to parent P-Aim 2c. We will test the efficiency of the design in vitro in murine BMM. This revision proposes therefore the following four specific aims:
Aim 1 : Construction of a mathematical model for the TLR2 gene network;
Aim 2 : Construction of a mouse BMM metabolic model;
Aim 3 : Design of genetic modifications affecting the response to infection in OB cells;
Aim 4 : In vitro testing of genetic modifications in mouse cell lines. The four specific aims listed above will lead to a significant increase in the scope of the overall project. By combining state-of-art computational approaches with experimental trials, we will be able to predict the cause of the phenotypic differences between the OB and LN cells, and try experimentally only genes that pass our in silico tests. This is in contrast with the initial scope of the parent aim P-Aim 2b, which was to identify genes that are differentially expressed and then directly test the effect of their perturbations experimentally. By including metabolic analysis, we will be able to better understand the effect of nutrition on the response to infection, and link nutrition to the gene expression response. In particular, we will quantify the effect of FFA, as initially proposed in the parent aim P-Aim 2c. At the end of this two-year revision, we will be in position of testing efficacy of our candidates in our periodontal animal model in hopes of moving to human clinical trials.

Public Health Relevance

This competitive revision project will test the hypothesis that diet-induced obesity alters the immune response to Porphyromonas gingivalis in obese animals in response to Notice Number NOT-OD-09-058. The results of these 2 year supplement should provide novel and crucial data that will deepen our understanding of the pathway- specific mechanisms involved in the diet-induced regulation of host innate immune response to pathogens. New knowledge gained from the proposed studies will likely have profound implications for the design of new therapies and modalities aimed at reducing clinical sequelae associated with obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
3R01DE015989-05A2S1
Application #
7809374
Study Section
Special Emphasis Panel (ZRG1-MOSS-K (95))
Program Officer
Lumelsky, Nadya L
Project Start
2009-09-23
Project End
2013-01-31
Budget Start
2009-09-23
Budget End
2013-01-31
Support Year
5
Fiscal Year
2009
Total Cost
$454,821
Indirect Cost
Name
Boston University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Amar, S; Engelke, M (2015) Periodontal innate immune mechanisms relevant to atherosclerosis. Mol Oral Microbiol 30:171-85
Richard, Guilhem; Trivedi, Niraj; Belta, Calin et al. (2013) Partial restoration of macrophage alteration from diet-induced obesity in response to Porphyromonas gingivalis infection. PLoS One 8:e70320
Richard, Guilhem; Belta, Calin; Julius, A Agung et al. (2012) Controlling the outcome of the Toll-like receptor signaling pathways. PLoS One 7:e31341
Zhou, Qingde; Leeman, Susan E; Amar, Salomon (2011) Signaling mechanisms in the restoration of impaired immune function due to diet-induced obesity. Proc Natl Acad Sci U S A 108:2867-72
Chang, H; Richard, G; Julius, A A et al. (2011) An application of monotone functions decomposition to the reconstruction of gene regulatory networks. Conf Proc IEEE Eng Med Biol Soc 2011:2430-3
Yu, Wen-Han; Hu, Han; Zhou, Qingde et al. (2010) Bioinformatics analysis of macrophages exposed to Porphyromonas gingivalis: implications in acute vs. chronic infections. PLoS One 5:e15613
Zelkha, Sami A; Freilich, Robert W; Amar, Salomon (2010) Periodontal innate immune mechanisms relevant to atherosclerosis and obesity. Periodontol 2000 54:207-21
Mazumdar, Varun; Snitkin, Evan S; Amar, Salomon et al. (2009) Metabolic network model of a human oral pathogen. J Bacteriol 191:74-90
Zhou, Qingde; Leeman, Susan E; Amar, Salomon (2009) Signaling mechanisms involved in altered function of macrophages from diet-induced obese mice affect immune responses. Proc Natl Acad Sci U S A 106:10740-5
Lowry, Matthew H; McAllister, Brian P; Jean, Jyh-Chang et al. (2008) Lung lining fluid glutathione attenuates IL-13-induced asthma. Am J Respir Cell Mol Biol 38:509-16

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