Quickscan 2018

13 April 2018
#GIT2 #Thymus #Aging
Aging is one of the most complex processes in biology. The molecular events that comprise aging are organized into ‘small-world’ networks that are interconnected by keystone or ‘hub’ proteins. The Stuart Maudsley Lab (VIB-UAntwerp Center for Molecular Neurology) has demonstrated that the G protein-coupled receptor kinase interacting protein 2 (GIT2) acts as an aging keystone. Genomic alteration of GIT2 expression in mice accelerates systemic aging and induces premature thymic involution – a classical marker of aging. GIT2- mediated immune dysfunction is caused by altered clock gene time sensing across multiple tissues.
Siddiqui et al., Aging 2017

#Atopic march #Glucocorticoid receptor #Peroxisome proliferator-activated receptor μ
Children with atopic dermatitis (AD) show an increased risk of developing asthma later in life, a phenomenon known as the atopic march. With Karolien De Bosscher (VIB-UGent Center for Biotechnology) and Hamida Hammad (VIB-UGent Center for Inflammation Research) as her PhD promotors Julie Deckers (VIB-UGent Center for Biotechnology) developed a mouse model and found that prior HDM-induced skin inflammation
aggravates the subsequent allergic airway inflammation and induces a mixed Th2/Th17 response. Although it does not interfere with the Th2 component of the atopic march, cutaneous GR/PPARγ co-activation represents a potent remedy against allergic skin inflammation and worsening of the atopic march by counteracting the Th17 response. These findings have given us a deeper understanding of the complexity of the atopic march and a starting point to further investigate its driving mechanisms in order to develop alternative therapies that could halt this phenomenon.
Deckers et al., J. Invest. Dermatol. 2017

#Plant growth regulation #Short-term stress response #Gene regulatory networks
Plants have to cope with environmental fluctuations and accordingly fine-tune their growth and development through the regulation of molecular networks that are largely unknown. The lab of Dirk Inzé (VIB-UGent Center for Plant Systems Biology) detailed a complex, highly interconnected network of 20 Arabidopsis transcription factors at the basis of leaf growth inhibition upon mild osmotic stress. Phenotypic analysis identified novel growthpromoting genes, some of which stimulated organ growth even more when combined. This work offers new perspectives for selecting stress-tolerant crops.
Van den Broeck et al., Mol. Syst. Biol. 2017

#Plant gene regulation #Systems biology
Although various experimental methods exist to map gene regulatory networks in Arabidopsis thaliana, their limited throughput renders our knowledge about regulators for many genes incomplete. PhD student Shubhada Kulkarni from the Klaas Vandepoele group (VIB-UGent Center for Plant Systems Biology) introduced TF2Network, a tool that exploits the vast amount of transcription factor binding site information to detect potential regulators for a set of co-expressed or functionally related genes.
Kulkarni et al., Nucl. Acids Res. 2018

#GlycoCirrhoTest #Hepatocellular carcinoma #Cirrhosis
In cooperation with the group of Hans Van Vlierberghe (UGent/UZ Gent), the Nico Callewaert Lab (VIB-UGent Center for Medical Biotechnology) assessed GlycoCirrhoTest for the risk of hepatocellular carcinoma (HCC) development in compensated cirrhosis patients. This study demonstrates that a simple serum blood test based on the analysis of serum glycomics predicts a 5-year 12-fold enhanced risk for the development of HCC
in these patients. This enables a more intensive screening for HCC.
Verhelst et al., Clin. Cancer Res. 2017

#C9orf72 #ALS #RNAtoxicity
C9orf72 expansion is the most frequent genetic cause of ALS and FTD, but it is unclear which pathogenic mechanism it elicits: repeat RNA toxicity or dipeptide protein (DPR) toxicity. The team of Ludo Van Den Bosch (VIB-KU Leuven Center for Brain & Disease Research) used a zebrafish model to answer this question, and found that neurodegeneration arises, at least in part, from RNA toxicity that is independent of DPRs.
Assuming that both play a role, the team proposes that approaches targeting both modalities have the highest therapeutic potential, as opposed to targeting DPR toxicity alone.
Swinnen et al., Acta Neuropathol. 2018

#Pro-inflammatory human cytokine # IL-23 #IL-12Rß1
The IL-23:IL-17 axis is highly relevant to the development of inflammatory diseases such as psoriasis. PhD student Yehudi Bloch from the Savvas Savvides Lab (VIB-UGent Center for Inflammation Research) investigated the assembly principles and structure of the IL-23 receptor complex with the support of local and international research groups. Yehudi Bloch: “We determined the structure of IL-23 bound to IL-23R and propose an assembly mechanism whereby conformational sampling and restraining of the cytokine is key to the assembly of the signaling complex. Our insights will hopefully help in the development of new therapeutic
strategies against IL-23.”
Bloch et al., Immunity 2017

#Cancer Immunotherapy #Interferon
Clinical use of type I interferon (IFN) is curbed by its complex toxicity pattern. Anje Cauwels and her colleagues from the Jan Tavernier Lab (VIB-UGent Center for Medical Biotechnology) developed AcTaferons (AFN = Activity-on-Target IFN) displaying focused, cell-specific signaling. AFN-targeting using a tumor-specific antigen prevents tumor growth, and when targeted to dendritic cells a broad-spectrum antitumor effect is seen against melanoma, breast carcinoma and lymphoma, all without any detectable toxic side effects. In combination therapies, complete tumor regression and immunity are obtained. Hence, AFNs represent a new class of safe and generic, off-the-shelf cancer immunotherapeutics.
Cauwels et al., Cancer Res. 2018, Cauwels et al., OncoImmunology 2018

#Vessel dysmorphia #Glioma #Stroma
Gliomas are aggressive and abundantly vascularized tumors. Longitudinal intravital imaging revealed progressive vessel dysmorphia during glioma growth due to dynamic macrophage recruitment and re-polarization. The Holger Gerhardt lab (VIB-KU Leuven Center for Cancer Biology) found that targeting this stroma response resulted in vessel normalization and improved efficacy of chemotherapy, suggesting that the combination of these therapeutic modalities could improve the outcome of glioma treatment in the clinic.
Mathivet et al., EMBO Mol. Med. 2017

#Leukemia #JAK3 #Mutations
PhD student Sandrine Degryse and her colleagues of the Jan Cools Lab (VIB-KU Leuven Center for Cancer
Biology) observed that one-third of JAK3-mutant T-cell leukemia cases harbor two JAK3 mutations, some of which are monoallelic and others that are biallelic. Analysis of these double mutants in primary mouse T cells demonstrated that JAK3 mutants can increase their limited oncogenic potential through the acquisition of additional mutations in the same JAK3 allele, or by losing the wild type allele.
Degryse et al., Blood 2017

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