Mouse strains are frequently used to model human disease states, to test the efficiency of drugs and therapeutic principles. However, the direct translation of murine experimental data to human pathological events often fails due to sufficient differences in the organization of the immune system of both species. Here we give a short overview of the principle differences between mice and humans in defense strategies against pathogens and mechanisms involved in response to pathogenic microorganisms and other activators of the immune system. While in human blood mechanisms of immune resistance are highly prevailed, tolerance mechanisms dominate for the defense against pathogenic microorganisms in mouse blood. Further on, species-related differences of immune cells mainly involved in innate immune response as well as differences to maintain oxidative homeostasis are also considered. A number of disease scenarios in mice are critically reflected for their suitability to serve as a model for human pathologies. Due to setbacks in these studies, novel mouse models were created to bridge the immune system of both species: humanized mice. Accordingly, a special section of this review is devoted to new results applying humanized mouse models taking limitations and prospects into account.

Optical coherence tomography (OCT) is a minimally-invasive imaging modality that generates high resolution cross-sectional images of tissue. The present study employed a 2 mm diameter endoscopic spectral domain OCT system in the in vivo evaluation of the drugs α-Difluoromethylornithine and Sulindac as chemopreventive and chemotherapeutic agents in a mouse model of sporadic colorectal cancer. 30 mm lateral images of each colon at eight different rotations were obtained at five different time points. Visual analysis of the images was performed to determine the number and size of discrete adenomas, with gross photos and histology serving as gold standard confirmation of the final imaging time point. When applied for chemoprevention, DFMO and Sulindac both significantly reduced the incidence of adenoma, appearing to interact additively in the prevention of tumorigenesis. For chemotherapy, however, only Sulindac had a significant effect on the number of adenoma and neither DFMO nor Sulindac significantly affected tumor growth.

Of the thousands of dividing progenitor cells (PCs) generated daily in the adult brain only a very small proportion survive to become mature neurons through the process of neurogenesis. Identification of the mechanisms that regulate cell death associated with neurogenesis would aid in harnessing the potential therapeutic value of PCs. Apoptosis, or programmed cell death, is suggested to regulate death of PCs in the adult brain as overexpression of B-cell lymphoma 2 (Bcl-2), an anti-apoptotic protein, enhances the survival of new neurons. To directly assess if Bcl-2 is a regulator of apoptosis in PCs, this study examined the outcome of removal of Bcl-2 from the developing PCs in the adult mouse brain. Retroviral mediated gene transfer of Cre into adult floxed Bcl-2 mice eliminated Bcl-2 from developing PCs and resulted in the complete absence of new neurons at 30 days post viral injection. Similarly, Bcl-2 removal through the use of nestin-induced conditional knockout mice resulted in reduced number of mature neurons. The function of Bcl-2 in the PCs was also dependent on Bcl-2-associated X (BAX) protein, as demonstrated by an increase in new neurons formed following viral-mediated removal of Bcl-2 in BAX knockout mice. Together these findings demonstrate that Bcl-2 is an essential regulator of neurogenesis in the adult hippocampus.

Hyaluronidase 2 (HYAL2) is a GPI-linked protein that is proposed to initiate the degradation of hyaluronan (HA), a major extracellular matrix component of many vertebrate tissues. Hyal2 knockout (KO) mice displayed craniofacial abnormalities and severe preweaning lethality. 54% of the surviving KOs developed a grossly dilated left or right atrium, requiring euthanasia, by 3 months of age. We hypothesize that the absence of HYAL2 leads to the accumulation of HA in organs/tissues where HA is normally abundant resulting in developmental defects and organs dysfunction. Molecular and histological analysis of HYAL2 KO hearts demonstrated extracellular accumulation of high molecular mass (HMM) HA in the heart valves, myocardium, serum and lungs which was associated with severe cardiopulmonary dysfunction. Further, structural and functional analyses of Hyal2 KO mouse hearts using high-frequency ultrasound revealed atrial dilation accompanied by diastolic dysfunction that was evident as early as 4 weeks of age, and progressed with age. Further, 50% of HYAL2 KO mice exhibited a triatrial heart (cor-triatriatum). Histological analyses revealed that the atrial dilation was the result of excess tissue, and did not correlate with the presence of cor triatrium. Hyal2 KO mice were found to have increased numbers of mesenchymal cells at early stages of development, presumably due to the presence of excess HA, that lead to cardiac dysfunction. Further examination of HYAL2 distribution in a broad range of mouse tissues, and accumulation of HA in its absence demonstrated that HYAL2 is mainly localized to endothelial cells and some specialized epithelial cells, and plays a major role in HMM-HA degradation. These studies demonstrated that HYAL2 is important for HA degradation and organ development. In the longer term, our findings will be valuable for understanding pathologies associated with the disruption of HA catabolism, and potentially in the identification of HYAL2-deficient patients. / May 2016

<p>Approximately 50% of all patients with cancer receive radiation therapy at some point during the course of their illness. Despite advances in radiation delivery and treatment planning, normal tissue toxicity often limits the ability of radiation to eradicate tumors. The tumor microenvironment consists of tumor cells and stromal cells such as endothelial cells that contribute to tumor initiation, progression and response to therapy. Although endothelial cells can contribute to normal tissue injury following radiation, the contribution of stromal cells to tumor response to radiation therapy remains controversial. To investigate the contribution of endothelial cells to the radiation response of primary tumors, we have developed the technology to contemporaneously mutate different genes in the tumor cells and stromal cells of a genetically engineered mouse model of soft tissue sarcoma. Using this dual recombinase technology, we deleted the DNA damage response gene <italic>Atm</italic> in sarcoma and heart endothelial cells. Although deletion of <italic>Atm</italic> increased cell death of proliferating tumor endothelial cells, <italic>Atm</italic> deletion in quiescent endothelial cells of the heart did not sensitize mice to radiation-induced myocardial necrosis. In addition, the ATM inhibitor NVP-BEZ235 selectively radiosensitized primary sarcomas, demonstrating a therapeutic window for inhibiting ATM during radiation therapy. Sensitizing tumor endothelial cells to radiation by deleting <italic>Atm</italic> prolonged tumor growth delay following a non-curative dose of radiation, but failed to increase local control. In contrast, deletion of <italic>Atm</italic> in tumor parenchymal cells increased the probability of tumor eradication. These results demonstrate that tumor parenchymal cells rather than endothelial cells are the critical targets that regulate tumor eradicaiton by radiation therapy.</p> / Dissertation

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In the US, the incidence and mortality rates of hepatocellular carcinoma (HCC) are alarmingly increasing since no effective therapy is available for the advanced disease. Activation of IGF signaling is a major oncogenic event in diverse cancers, including HCC. Insulin-like growth factor binding protein-7 (IGFBP7) inhibits IGF signaling by binding to IGF-1 receptor (IGF-1R) and functions as a potential tumor suppressor for hepatocellular carcinoma (HCC). IGFBP7 abrogates tumors by inducing cancer-specific senescence and apoptosis and inhibiting angiogenesis. We now document that Igfbp7 knockout (Igfbp7-/- ) mouse shows constitutive activation of IGF signaling, presents with pro-inflammatory and immunosuppressive microenvironment, and develops spontaneous tumors in lungs and liver and markedly accelerated carcinogen-induced HCC. Loss of Igfbp7 resulted in increased proliferation and decreased senescence in hepatocytes and mouse embryonic fibroblasts that could be blocked by an IGF-1 receptor inhibitor. A significant inhibition of genes regulating immune surveillance was observed in Igfbp7-/- livers which was associated with marked inhibition in antigen cross presentation by Igfbp7-/- dendritic cells. IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immune competent mice, which could be abolished by depletion of CD4+ or CD8+ T lymphocytes. Our studies unravel modulation of immune response as a novel component of pleiotropic mechanisms by which IGFBP7 suppresses HCC. Even though HCC has an immunosuppressive milieu, immune targeted therapies are beginning to demonstrate significant objective responses in clinical trials. IGFBP7 might be an effective anti-HCC therapeutic by directly inhibiting cancer cells and stimulating an anti-tumor immune response.

Diabetes mellitus affects nearly 300 million people in the world. The development of diabetes is caused by dysfunction or by reduction of insulin-producing β-cells that are part of the endocrine pancreas. Therefore, the most critical step for understanding the pathophysiology of diabetes and for restoring lost β cells is the identification of molecular cues that specify the cellular phenotype in the pancreas. This work is based on the hypothesis that the transcription factor NEUROD1 is a key factor for the development of the pancreas and for the maintenance of endocrine tissue function. Neurod1 conditional KO mutants (Neurod1CKO) were generated using the Cre-loxP system by crossing floxed Neurod1 mice with Isl1-Cre line. Immunohistochemical analyses of the pancreas at embryonic day 17.5 and postnatal day 0 showed that the deletion of Neurod1 negatively affected the development, organization of endocrine tissue, and total mass of pancreatic endocrine cells. To better understand molecular changes, quantitative PCR was used to analyse mRNA expression in the developing pancreas at the age of embryonic day 14.5 and postnatal day 1. Genes important for the development and function of the pancreas have been selected for the study of expression changes. These analyses showed changes in expression of genes...