Mouse modeling for anxiety disorders in older adults

Anxiety disorders are common in older adults and are strongly associated with increased risk for numerous age-related conditions. Preclinical mechanistic data are needed to identify more specific therapeutic targets for treating and preventing these disorders. Mice serve as excellent preclinical models as they have been used extensively in aging studies, and behavioral tests have been developed. A panel of tests would capture the important clinical aspects of apathy, anxiety, and psychomotor behavior and allow longitudinal testing strategies in a rigorous and minimally stressful manner.

Epigenetic dysregulation in myeloid malignancies

Epigenetic deregulation is now a well-recognized -though not yet fully understood- mechanism that contributes to the development and progression of myeloid malignancies. In the past 15 years, next generation sequencing studies have revealed patterns of aberrant DNA methylation, altered chromatin states, and mutations in chromatin modifiers across the spectrum of myeloid malignancies. Studies into the mechanisms that drive these diseases through mouse modeling have helped identify new avenues for therapeutic interventions, from initial treatment to resistant, relapsed disease. This is particularly significant when chemotherapy with cytotoxic agents remains the general standard of care. In this review, we will discuss some of the recent findings of epigenetic mechanisms and how these are informing the development of more targeted strategies for therapeutic intervention in myeloid malignancies.

Detection of Alzheimer’s disease-related neuroinflammation by a PET ligand selective for glial versus vascular translocator protein

A substantial and constitutive expression of translocator protein (TSPO) in cerebral blood vessels hampers the sensitive detection of neuroinflammation characterized by greatly induced TSPO expression in activated glia. Here, we conducted in vivo positron emission tomography (PET) and in vitro autoradiographic imaging of normal and TSPO-deficient mouse brains to compare the binding properties of 18F-FEBMP, a relatively novel TSPO radioligand developed for human studies based on its insensitivity to a common polymorphism, with 11C-PK11195, as well as other commonly used TSPO radioligands including 11C-PBR28, 11C-Ac5216 and 18F-FEDAA1106. TSPO in cerebral vessels of normal mice was found to provide a major binding site for 11C-PK11195, 11C-PBR28 and 18F-FEDAA1106, in contrast to no overt specific binding of 18F-FEBMP and 11C-Ac5216 to this vascular component. In addition, 18F-FEBMP yielded PET images of microglial TSPO with a higher contrast than 11C-PK11195 in a tau transgenic mouse modeling Alzheimer’s disease (AD) and allied neurodegenerative tauopathies. Moreover, TSPO expression examined by immunoblotting was significantly increased in AD brains compared with healthy controls, and was well correlated with the autoradiographic binding of 18F-FEBMP but not 11C-PK11195. Our findings support the potential advantage of comparatively glial TSPO-selective radioligands such as 18F-FEBMP for PET imaging of inflammatory glial cells.

Genomic and Functional Regulation of TRIB1 Contributes to Prostate Cancer Pathogenesis

Prostate cancer is the most frequent malignancy in European men and the second worldwide. One of the major oncogenic events in this disease includes amplification of the transcription factor cMYC. Amplification of this oncogene in chromosome 8q24 occurs concomitantly with the copy number increase in a subset of neighboring genes and regulatory elements, but their contribution to disease pathogenesis is poorly understood. Here we show that TRIB1 is among the most robustly upregulated coding genes within the 8q24 amplicon in prostate cancer. Moreover, we demonstrate that TRIB1 amplification and overexpression are frequent in this tumor type. Importantly, we find that, parallel to its amplification, TRIB1 transcription is controlled by cMYC. Mouse modeling and functional analysis revealed that aberrant TRIB1 expression is causal to prostate cancer pathogenesis. In sum, we provide unprecedented evidence for the regulation and function of TRIB1 in prostate cancer.

MAPK-induced miR-29 targets MAFG and suppresses melanoma development

ABSTRACTThe tumor suppressive miR-29 family of microRNAs is encoded by two clusters, miR-29b1∼a and miR-29b2∼c, and is regulated by several oncogenic and tumor suppressive stimuli. Here we investigated whether oncogenic MAPK hyperactivation regulates miR-29 abundance and how this signaling axis impacts melanoma development. Using mouse embryonic fibroblasts and human melanocytes, we found that oncogenic MAPK signaling stimulates p53-independent and p53-dependent transcription of pri-miR-29b1∼a and pri-miR-29b2∼c, respectively. Expression analyses revealed that while pri-miR-29a∼bl remains elevated, pri-miR-29b2∼c levels decrease during melanoma progression. Using a rapid mouse modeling platform, we showed that inactivation of miR-29 in vivo accelerates melanoma development and decreases overall survival. We identified the transcription factor MAFG as a bona fide miR-29 target that has oncogenic potential in melanocytes and is required for growth of melanoma cells. Our findings suggest that MAPK-induced miR-29 contributes to a tumor suppressive barrier by targeting MAFG, which is overcome by attenuation of miR-29b2∼c expression.