My career goal is to direct an independent research laboratory exploring the molecular mechanisms mediating host defense and inflammation. During inflammatory responses, both G protein-coupled (GPCRs) and innate immune receptors are activated simultaneously, and each can activate diverse cellular signals. The overall hypothesis is that inflammatory GPCR signaling interacts with and modifies many components of the macrophage Toll-like receptor (TLR) activation pathway, ultimately enhancing activation of the pro-inflammatory transcription factor nuclear factor kappa B (NFkB). This is supported by the preliminary finding that leukotriene B4 (LTB4) ligation of its GPCR BLT1 enhances the TLR- dependent activation of NFkB. There are many potential interactions between GPCR and TLR signaling that might combinatorially determine the state of NFkB activation. To discover such interactions, we propose an interdisciplinary approach combining experimentation with systems biology to model integrative networks that are capable of being tested experimentally.The general plan of this proposal is to acquire knowledge and skills during my initial two years of mentored training using BLT1-TLR interactions as a model, which will be extended to other classes of GPCRs during the independent phase. To test our hypothesis, the following Specific Aims are proposed: K99 period;
Aim 1 : Determine the importance of LTB4/BLT1 signaling (kinases, ROI generation) to TLR-dependent NFkB activation, Aim 2: Examine the effects of LTB4/BLT1 signaling on the expression of TLRs/IL-1beta receptors and their adaptors, Aim 3: Develop computational models (equations) involving the signaling programs induced by BLT1 during Mo TLR responses. R00 period:
Aim 4 : Based on the findings obtained in the K99 period, we want to further investigate the importance of Gai protein-coupled receptors other than BLT1 in TLR-induced NFkB activation, Aim 5: Computationally model cellular signaling networks (GPCR and TLRs) that regulate NFkB activation in order to formulate testable hypotheses. This proposal will provide new insights into the coordination of macrophage activation in inflammation, and will foster my development into an independent investigator.

Public Health Relevance

Our proposal have direct translational importance, since GPCRs, TLRs and NFkB are major targets of therapeutic interventions and the development of mathematical models could unlock more specific strategies to treat both overwhelming as well as immunosuppressive states by employing inhibitors to block inflammatory responses, as well as by adding exogenous GPCR agonists to enhance inflammation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Career Transition Award (K99)
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Special Emphasis Panel (ZHL1-CSR-Z (M2))
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Sarkar, Rita
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Brandt, Stephanie L; Wang, Sue; Dejani, Naiara N et al. (2018) Excessive localized leukotriene B4 levels dictate poor skin host defense in diabetic mice. JCI Insight 3:
Piñeros Alvarez, Annie Rocio; Glosson-Byers, Nicole; Brandt, Stephanie et al. (2017) SOCS1 is a negative regulator of metabolic reprogramming during sepsis. JCI Insight 2:
Filgueiras, Luciano Ribeiro; Brandt, Stephanie L; Ramalho, Theresa Raquel de Oliveira et al. (2017) Imbalance between HDAC and HAT activities drives aberrant STAT1/MyD88 expression in macrophages from type 1 diabetic mice. J Diabetes Complications 31:334-339
Ishizuka, Edson K; Filgueiras, Luciano Ribeiro; Rios, Francisco J et al. (2016) PAFR activation of NF-?B p65 or p105 precursor dictates pro- and anti-inflammatory responses during TLR activation in murine macrophages. Sci Rep 6:32092
Zoccal, Karina F; Sorgi, Carlos A; Hori, Juliana I et al. (2016) Opposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality. Nat Commun 7:10760
Dejani, Naiara N; Brandt, Stephanie L; Piñeros, Annie et al. (2016) Topical Prostaglandin E Analog Restores Defective Dendritic Cell-Mediated Th17 Host Defense Against Methicillin-Resistant Staphylococcus Aureus in the Skin of Diabetic Mice. Diabetes 65:3718-3729
Wang, Zhuo; Brandt, Stephanie; Medeiros, Alexandra et al. (2015) MicroRNA 21 is a homeostatic regulator of macrophage polarization and prevents prostaglandin E2-mediated M2 generation. PLoS One 10:e0115855
Filgueiras, Luciano Ribeiro; Brandt, Stephanie L; Wang, Soujuan et al. (2015) Leukotriene B4-mediated sterile inflammation promotes susceptibility to sepsis in a mouse model of type 1 diabetes. Sci Signal 8:ra10
Carrasco, Sebastian E; Troxell, Bryan; Yang, Youyun et al. (2015) Outer surface protein OspC is an antiphagocytic factor that protects Borrelia burgdorferi from phagocytosis by macrophages. Infect Immun 83:4848-60
da Silva-Souza, Hercules Antônio; Lira, Maria Nathalia de; Costa-Junior, Helio Miranda et al. (2014) Inhibitors of the 5-lipoxygenase arachidonic acid pathway induce ATP release and ATP-dependent organic cation transport in macrophages. Biochim Biophys Acta 1838:1967-77

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