Alterations in host innate immune function within the lung may predispose to opportunistic infections that cause great morbidity and mortality during HIV infection. Mathematical models are needed to help understand the complex interactions of cytokines, cytokine antagonists, and chemokines that affect the innate host immune response within the lung during HIV infection. To date, analyses have been limited to descriptions of how HIV affects single or small sets of these molecules, instead of the larger network that acts in a coordinated manner to affect host immunity. Our group has developed """"""""reverse engineering"""""""" methods to model networks of interacting proteins and mRNA. We will use these reverse engineering methods to determine the structure of the cytokine/chemokine networks in the lung, how these are altered during HIV infection, and after treatment with highly active antiretroviral therapy (HAART). The reverse engineering algorithms suggest the most efficient way to resolve the network structure through an iterative process in which analysis of data from one experiment informs the design of the next experiment. Specifically, we will create mathematical models of cytokine/chemokine networks, using reverse engineering methods, in cell lines (U1 and U937) and in AMs from HIV+ subjects (with or without HAART) and HIV- subjects. This will be accomplished by performing a series of experiments in which we perturb different components of the cytokine/chemokine networks, measure changes in the components of the network, and apply the reverse engineering algorithms to determine the next most informative perturbations to resolve the network structure. The components of the network that will be both measured and perturbed include selected cytokines and chemokines, signaling pathway molecules, transcription factors, and mRNA for these moieties. Identification of the most central molecules in these linked systems may suggest new therapeutic or vaccine approaches to bolster the host immune response to HIV.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076114-04
Application #
7118614
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Peavy, Hannah H
Project Start
2003-09-26
Project End
2009-02-28
Budget Start
2006-09-01
Budget End
2009-02-28
Support Year
4
Fiscal Year
2006
Total Cost
$446,200
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
Morrow, Jarrett D; Cho, Michael H; Platig, John et al. (2018) Ensemble genomic analysis in human lung tissue identifies novel genes for chronic obstructive pulmonary disease. Hum Genomics 12:1
Sakornsakolpat, Phuwanat; Morrow, Jarrett D; Castaldi, Peter J et al. (2018) Integrative genomics identifies new genes associated with severe COPD and emphysema. Respir Res 19:46
Morrow, Jarrett D; Glass, Kimberly; Cho, Michael H et al. (2018) Human Lung DNA Methylation Quantitative Trait Loci Colocalize with Chronic Obstructive Pulmonary Disease Genome-Wide Association Loci. Am J Respir Crit Care Med 197:1275-1284
Sharma, Amitabh; Kitsak, Maksim; Cho, Michael H et al. (2018) Integration of Molecular Interactome and Targeted Interaction Analysis to Identify a COPD Disease Network Module. Sci Rep 8:14439
Radder, Josiah E; Gregory, Alyssa D; Leme, Adriana S et al. (2017) Variable Susceptibility to Cigarette Smoke-Induced Emphysema in 34 Inbred Strains of Mice Implicates Abi3bp in Emphysema Susceptibility. Am J Respir Cell Mol Biol 57:367-375
Busch, Robert; Hobbs, Brian D; Zhou, Jin et al. (2017) Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects. Am J Respir Cell Mol Biol 57:35-46
Morrow, Jarrett D; Zhou, Xiaobo; Lao, Taotao et al. (2017) Functional interactors of three genome-wide association study genes are differentially expressed in severe chronic obstructive pulmonary disease lung tissue. Sci Rep 7:44232
Dodd, James W; Novotny, Paul; Sciurba, Frank C et al. (2015) Executive Function, Survival, and Hospitalization in Chronic Obstructive Pulmonary Disease. A Longitudinal Analysis of the National Emphysema Treatment Trial (NETT). Ann Am Thorac Soc 12:1473-81
Kaplan, Robert M; Sun, Qiankun; Ries, Andrew L (2015) Quality of well-being outcomes in the National Emphysema Treatment Trial. Chest 147:377-387
Cho, Michael H; McDonald, Merry-Lynn N; Zhou, Xiaobo et al. (2014) Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis. Lancet Respir Med 2:214-25

Showing the most recent 10 out of 30 publications