The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.

mTOR Signaling in Growth Control and Disease

mTOR signaling in growth control and disease.

In certain aspects, the invention relates to methods for identifying compounds which modulate Akt activity mediated by the rictor-mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activity.

http://science.sciencemag.org/content/sci/307/5712/1098.full.pdf

Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex

The evolutionarily conserved checkpoint protein kinase, TOR (target of rapamycin), has emerged as a major effector of cell growth and proliferation via the regulation of protein synthesis. Work in the last decade clearly demonstrates that TOR controls protein synthesis through a stunning number of downstream targets. Some of the targets are phosphorylated directly by TOR, but many are phosphorylated indirectly. In this review, we summarize some recent developments in this fast-evolving field. We describe both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis. We also summarize the roles of mTOR in the control of cell growth and proliferation, as well as its relevance to cancer and synaptic plasticity.

/pdf/upstream-and-downstream-of-mtor-2v5cvgfhmb.pdf

Upstream and downstream of mTOR

mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth Machinery

Objective This study aimed to develop a functional model of subglottic stenosis by inducing direct airway irritation in transplanted mouse laryngotracheal complexes. Methods Laryngotracheal complexes from C57BL/6 mice were harvested and divided into three groups: uninjured, mechanically injured and chemically injured. Donor laryngotracheal complexes from each group were placed in dorsal subcutaneous pockets of recipient mice. Each week, the transplanted laryngotracheal complexes were harvested, and tissues were fixed, sectioned, and stained with haematoxylin and eosin. Representative slides were reviewed by a blinded pathologist, to determine the formation of granulation tissue, and graded as to the degree of granulation formation. Results Direct airway irritation induced granulation tissue formation under the disrupted epithelium of airway mucosa; this was seen as early as two weeks after chemical injury. Conclusion Results indicate that granulation tissue formation in a murine model may be an efficient tool for investigating the development and treatment of subglottic stenosis.

A murine model of subglottic granulation.

http://www.jaci-inpractice.org/article/S2213219822005013/pdf

Impact of dupilumab on SNOT-22 sleep and function scores in CRSwNP.

Patients with aspirin‐exacerbated respiratory disease (AERD) are among the most challenging rhinologic patients to treat. AERD has a complex inflammatory milieu of lipid mediators and cytokines. In this study we evaluated cytokine differences in the complex AERD environment at the mucus, epithelial, and tissue levels.

Steroid affected cytokines in aspirin‐exacerbated respiratory disease

Inflammatory masses located in the lateral aspect of the frontal sinus often represent supraorbital ethmoid lesions. These lesions can often be approached endoscopically, sparing the patient an external incision. Knowledge of the anatomy, proper instrumentation, and meticulous surgical technique are needed for an endoscopic approach.

Surgical treatment of the lateral frontal sinus lesion

Bitter (T2R) and sweet/umami (T1R) taste receptors serve chemosensory roles throughout the body. In airway cilia, T2Rs detect bacterial metabolites to stimulate bactericidal nitric oxide. T1Rs in solitary chemosensory cells detect glucose in airway surface liquid (ASL) and bacterial D-stereoisomer amino acids to regulate antimicrobial peptides. Using differentiated air-liquid interface cultures of primary nasal cells, we show that the T1R3 receptor is also expressed in human and mouse nasal cell cilia. D-amino acids produced at low mM concentrations by Staphylococcus aureus activate T1R3 to decrease ASL glucose and increase apical glucose uptake by increasing GLUT2 and GLUT10 expression through a β-arrestin pathway. Our data suggests that T1R3 localized to cilia functions as an immune detector for D-amino acids to reduce ASL glucose and potentially limit bacterial growth. Given that glucose protected S. aureus against bactericidal NO produced during T2R activation, the reduced ASL glucose with T1R3 activation may also sensitize bacteria to other innate defenses. HIGHLIGHTS Nasal motile cilia express the T1R3 subunit of the sweet taste receptor S. aureus D-amino acids activate cilia T1R3 to enhance mucosal glucose uptake Reduced airway surface liquid glucose likely reduces S. aureus growth Reduced airway glucose also sensitizes S. aureus to epithelial NO production

Noam A. Cohen

Papers

A murine model of subglottic granulation.

Impact of dupilumab on SNOT-22 sleep and function scores in CRSwNP.

Steroid affected cytokines in aspirin‐exacerbated respiratory disease

Surgical treatment of the lateral frontal sinus lesion

Taste receptor T1R3 in nasal cilia detects Staphylococcus aureus D-amino acids to increase apical glucose uptake and enhance innate immunity