In central nervous system pathologies, including multiple sclerosis, stroke, spinal cord and traumatic injuries, scar formation consisting of reactive astrocytes and deposition of extracellular matrix is a major inhibitor of tissue repair. The molecular mechanisms that trigger astrocyte activation in nervous system disease remain incompletely characterized. We have shown that the neurotrophin receptor p75NTR regulates repair processes by inhibiting fibrin degradation and regulating cell differentiation. Our long-term goal is to characterize the molecular pathways that are responsible for the effects of p75NTR in nervous system pathogenesis, as a prerequisite for the development of therapeutic protocols that can specifically target p75NTR signaling and attenuate neuropathological disease processes. Our major hypothesis is that intramembrane proteolysis of p75NTR regulates TGF-? signaling to control astrocyte functions during development and disease. Our preliminary data demonstrate that a) the intracellular domain of p75NTR (p75ICD) is a novel component of the nuclear pore complex in astrocytes, b) p75NTR directly binds to the natively unfolded FG-domain of nucleoporin 153 (Nup153), c) TGF-? induces 3-secretase-dependant cleavage of p75NTR resulting in its translocation inside the nuclear pore, d) p75NTR regulates of Smad2, and e) p75NTR regulates astrocyte differentiation and TGF-? functions in the CNS in vivo.
Our specific aims are designed to test our working model, in which intramembrane cleavage of p75NTR results in remodeling of the nuclear pore complex that allows nucleocytoplasmic shuttling of Smad2 and induces astrocyte differentiation and activation. We employ a multiphaceted experimental design that includes transgenic models of TGF?-induced astrocyte activation, generation of new transgenic mice for cell-fate mapping of p75NTR - expressing cells, atomic force microscopy and three-dimensional electron tomography to determine the role of cleaved p75NTR in the dynamic remodeling of the nuclear pore complex in astrocytes, and biochemical experiments to define how p75NTR cleavage regulates Smad2 nucleocytoplasmic shuttling and its coupling to the TGF? transcriptional machinery. Identifying the molecular interplay between p75NTR and TGF? signaling pathways could potentially provide injury-specific targets for pharmacological intervention in a variety of diseases characterized by astrocyte scar formation and decreased capacity for tissue repair.
|Baeza-Raja, Bernat; Sachs, Benjamin D; Li, Pingping et al. (2016) p75 Neurotrophin Receptor Regulates Energy Balance in Obesity. Cell Rep 14:255-68|
|Akassoglou, Katerina; Agalliu, Dritan; Chang, Christopher J et al. (2016) Neurovascular and Immuno-Imaging: From Mechanisms to Therapies. Proceedings of the Inaugural Symposium. Front Neurosci 10:46|
|Zhang, Ming-Dong; Barde, Swapnali; Yang, Ting et al. (2016) Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels. Proc Natl Acad Sci U S A 113:E6686-E6695|
|Schachtrup, Christian; Ryu, Jae Kyu; Mammadzada, Könül et al. (2015) Nuclear pore complex remodeling by p75(NTR) cleavage controls TGF-? signaling and astrocyte functions. Nat Neurosci 18:1077-80|
|Le Moan, Natacha; Baeten, Kim M; Rafalski, Victoria A et al. (2015) Hypoxia Inducible Factor-1? in Astrocytes and/or Myeloid Cells Is Not Required for the Development of Autoimmune Demyelinating Disease eNeuro 2:|
|Gut, Philipp; Baeza-Raja, Bernat; Andersson, Olov et al. (2013) Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism. Nat Chem Biol 9:97-104|
|Chen, Wanqiu; Guo, Yi; Walker, Espen J et al. (2013) Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain. Arterioscler Thromb Vasc Biol 33:305-10|
|Baeza-Raja, Bernat; Eckel-Mahan, Kristin; Zhang, Luoying et al. (2013) p75 neurotrophin receptor is a clock gene that regulates oscillatory components of circadian and metabolic networks. J Neurosci 33:10221-34|
|Baeza-Raja, Bernat; Li, Pingping; Le Moan, Natacha et al. (2012) p75 neurotrophin receptor regulates glucose homeostasis and insulin sensitivity. Proc Natl Acad Sci U S A 109:5838-43|
|Merlini, Mario; Davalos, Dimitrios; Akassoglou, Katerina (2012) In vivo imaging of the neurovascular unit in CNS disease. Intravital 1:87-94|
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