Activated macrophages are a common hallmark of many inflammatory disease and play a significant role in the outcome of endotoxic shock. This proposal studies the down-regulation of macrophages by the Mer receptor tyrosine kinase using molecular and cellular methods, both in vivo and in vitro. The purpose of this proposal is to determine mechanisms by which Mer receptor tyrosine kinase inhibit macrophages and the consequence of the macrophage down-regulation on inflammation. The finding of this proposal would have broad implications toward attenuating inflammation associated with macrophages.
The Specific Aims are fourfold: 1). We will assess the molecular mechanism by which Mer inhibits LPS signal transduction. We will assess alteration in IkBalpha and IkBbeta in CD14 expressing CHO cell lines transfected with mer/kd and mer/WT constructs. We will also assess the role of Mer in JNK, p38 and ERK signaling pathways activated by LPS. Finally, we will assess whether Mer is interacting or affecting the cell surface expression of CD14. 2). We will determine how Mer modulates macrophages during inflammation. We will use mer/kd and mer/WT mice undergoing inflammation and assess severity of histology, cytokine profiles and macrophage activation. In addition, we propose a transgenic animal under the control of an inducible system to directly determine the consequence of Mer expression during inflammation. 3). We will determine whether the regulation of TNF-alpha-induced apoptosis by Mer is at a control point upstream of NF-kappaB. We will assess whether Mer alters levels of TRAFs to induce NF-kappaB. Also we will assess in vivo apoptosis in sites of inflammation mer/kd and mer/WT mice. 4). We will determine whether Mer activity can be correlated to macrophage activation from patients with chronic inflammation. Protein and phosphorylation assays of Mer will be assessed in macrophages isolated from patients. In addition, cytokine profiles and NF-kappaB will be quantified to determine correlation with inflammation.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Comprehensive Center (P60)
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University of North Carolina Chapel Hill
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Arce, R M; Caron, K M; Barros, S P et al. (2012) Toll-like receptor 4 mediates intrauterine growth restriction after systemic Campylobacter rectus infection in mice. Mol Oral Microbiol 27:373-81
Qian, Li; Wu, Hung-ming; Chen, Shih-Heng et al. (2011) ?2-adrenergic receptor activation prevents rodent dopaminergic neurotoxicity by inhibiting microglia via a novel signaling pathway. J Immunol 186:4443-54
Arce, R M; Diaz, P I; Barros, S P et al. (2010) Characterization of the invasive and inflammatory traits of oral Campylobacter rectus in a murine model of fetoplacental growth restriction and in trophoblast cultures. J Reprod Immunol 84:145-53
Maile, Laura A; Busby, Walker H; Nichols, Timothy C et al. (2010) A monoclonal antibody against alphaVbeta3 integrin inhibits development of atherosclerotic lesions in diabetic pigs. Sci Transl Med 2:18ra11
Lemmon, Christopher A; Chen, Christopher S; Romer, Lewis H (2009) Cell traction forces direct fibronectin matrix assembly. Biophys J 96:729-38
Qian, Li; Hu, Xiaoming; Zhang, Dan et al. (2009) beta2 Adrenergic receptor activation induces microglial NADPH oxidase activation and dopaminergic neurotoxicity through an ERK-dependent/protein kinase A-independent pathway. Glia 57:1600-9
Light, Kathleen C; Bragdon, Edith E; Grewen, Karen M et al. (2009) Adrenergic dysregulation and pain with and without acute beta-blockade in women with fibromyalgia and temporomandibular disorder. J Pain 10:542-52
Williams, Ray C (2008) Understanding and managing periodontal diseases: a notable past, a promising future. J Periodontol 79:1552-9
Qian, Li; Wei, Sung-Jen; Zhang, Dan et al. (2008) Potent anti-inflammatory and neuroprotective effects of TGF-beta1 are mediated through the inhibition of ERK and p47phox-Ser345 phosphorylation and translocation in microglia. J Immunol 181:660-8
Qian, Li; Flood, Patrick M (2008) Microglial cells and Parkinson's disease. Immunol Res 41:155-64

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