scholarly journals Mouse Models of Autism: Testing Hypotheses About Molecular Mechanisms

2011 ◽  
pp. 187-212 ◽  
Author(s):  
Florence I. Roullet ◽  
Jacqueline N. Crawley
Keyword(s):  
Mouse Models ◽  
Molecular Mechanisms ◽  
Testing Hypotheses

scholarly journals Early alterations of neurovascular unit in the retina in mouse models of tauopathy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Fan Xia ◽  
Yonju Ha ◽  
Shuizhen Shi ◽  
Yi Li ◽  
Shengguo Li ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Leukocyte Adhesion ◽  
Neurovascular Unit ◽  
Integrated Analysis ◽  
Therapeutic Effects ◽  
Retinal Ganglion ◽  
Potential Biomarker

AbstractThe retina, as the only visually accessible tissue in the central nervous system, has attracted significant attention for evaluating it as a biomarker for neurodegenerative diseases. Yet, most of studies focus on characterizing the loss of retinal ganglion cells (RGCs) and degeneration of their axons. There is no integrated analysis addressing temporal alterations of different retinal cells in the neurovascular unit (NVU) in particular retinal vessels. Here we assessed NVU changes in two mouse models of tauopathy, P301S and P301L transgenic mice overexpressing the human tau mutated gene, and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA). We found that retinal edema and breakdown of blood–retina barrier were observed at the very early stage of tauopathy. Leukocyte adhesion/infiltration, and microglial recruitment/activation were constantly increased in the retinal ganglion cell layer of tau transgenic mice at different ages, while Müller cell gliosis was only detected in relatively older tau mice. Concomitantly, the number and function of RGCs progressively decreased during aging although they were not considerably altered in the very early stage of tauopathy. Moreover, intrinsically photosensitive RGCs appeared more sensitive to tauopathy. Remarkably, TOMA treatment in young tau transgenic mice significantly attenuated vascular leakage, inflammation and RGC loss. Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal NVU, and vascular alterations occur more manifest and earlier than neurodegeneration in the retina. Oligomeric tau-targeted immunotherapy has the potential to treat tau-induced retinopathies. These data suggest that retinal NVU may serve as a potential biomarker for diagnosis and staging of tauopathy as well as a platform to study the molecular mechanisms of neurodegeneration.

PRDM16 Is a Compact Myocardium-Enriched Transcription Factor Required to Maintain Compact Myocardial Cardiomyocyte Identity in Left Ventricle

Circulation ◽  
2021 ◽  
Author(s):  
Tongbin Wu ◽  
Zhengyu Liang ◽  
Zengming Zhang ◽  
Canzhao Liu ◽  
Lunfeng Zhang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Single Cell ◽  
Rna Sequencing ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Left Ventricular ◽  
Ventricular Noncompaction ◽  
Chip Sequencing ◽  
Transcriptional Signature ◽  
Underlying Mechanisms

Background: Left ventricular noncompaction cardiomyopathy (LVNC) was discovered half a century ago as a cardiomyopathy with excessive trabeculation and a thin ventricular wall. In the decades since, numerous studies have demonstrated that LVNC primarily impacts left ventricles (LVs), and is often associated with LV dilation and dysfunction. However, owing in part to the lack of suitable mouse models that faithfully mirror the selective LV vulnerability in patients, mechanisms underlying susceptibility of LV to dilation and dysfunction in LVNC remain unknown. Genetic studies have revealed that deletions and mutations in PRDM16 cause LVNC, but previous conditional Prdm16 knockout mouse models do not mirror the LVNC phenotype in patients, and importantly, the underlying molecular mechanisms by which PRDM16 deficiency causes LVNC are still unclear. Methods: Prdm16 cardiomyocyte (CM)-specific knockout ( Prdm16 cKO ) mice were generated and analyzed for cardiac phenotypes. RNA sequencing and ChIP sequencing were performed to identify direct transcriptional targets of PRDM16 in CMs. Single cell RNA sequencing in combination with Spatial Transcriptomics were employed to determine CM identity at single cell level. Results: CM-specific ablation of Prdm16 in mice caused LV-specific dilation and dysfunction, as well as biventricular noncompaction, which fully recapitulated LVNC in patients. Mechanistically, PRDM16 functioned as a compact myocardium-enriched transcription factor, which activated compact myocardial genes while repressing trabecular myocardial genes in LV compact myocardium. Consequently, Prdm16 cKO LV compact myocardial CMs shifted from their normal transcriptomic identity to a transcriptional signature resembling trabecular myocardial CMs and/or neurons. Chamber-specific transcriptional regulation by PRDM16 was in part due to its cooperation with LV-enriched transcription factors Tbx5 and Hand1. Conclusions: These results demonstrate that disruption of proper specification of compact CM may play a key role in the pathogenesis of LVNC. They also shed light on underlying mechanisms of LV-restricted transcriptional program governing LV chamber growth and maturation, providing a tangible explanation for the susceptibility of LV in a subset of LVNC cardiomyopathies.

scholarly journals Induction and prevention of gastric cancer with combined Helicobacter pylori and capsaicin administration and DFMO treatment, respectively

2020 ◽  
Author(s):  
Faisal Aziz ◽  
Mingxia Xin ◽  
Yunfeng Gao ◽  
Josh Monts ◽  
Kjersten Monson ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Mouse Models ◽  
Chronic Gastritis ◽  
Molecular Mechanisms ◽  
Gastric Carcinogenesis ◽  
Lifestyle Changes ◽  
Host Susceptibility ◽  
Anti Inflammatory ◽  
H Pylori

Abstract Background: Gastric cancer risk evolves over time due to environmental, dietary, and lifestyle changes including Helicobacter pylori (H. pylori) infection and consumption of hot peppers (i.e. capsaicin). H. pylori infection promotes gastric mucosal injury in the early phase of capsaicin exposure. In addition, capsaicin consumption is reported to suppress immune function and increase host susceptibility to microbial infection. This relationship suggests a need to investigate the mechanism of how both H. pylori infection and capsaicin contribute to gastric inflammation and lead to gastric cancer. No previous experimental animal models have been developed to study this dual association. Here we developed a series of mouse models that progress from chronic gastritis to gastric cancer. C57-Balb/c mice were infected with the H. pylori (SS1) strain and then fed capsaicin (0.05% or 0.2g/kg/day) or not. Consequently, we investigated the association between H. pylori infection and capsaicin consumption during the initiation of gastric inflammation and the later development of gastric cancer. Tumor size and phenotype were analyzed to determine the molecular mechanism driving the shift from gastritis to stomach cancer. Gastric carcinogenesis was also prevented in these models using the ornithine decarboxylase inhibitor DFMO (2-difluoromethylornithine). Results: This study provides evidence showing that a combination of H. pylori infection and capsaicin consumption leads to gastric carcinogenesis. The transition from chronic gastritis to gastric cancer is mediated through interleukin-6 (IL-6) stimulation with an incidence rate of 50%. However, this progression can be prevented by treating with anti-inflammatory agents. In particular, we used DFMO to prevent gastric tumorigenesis by reducing inflammation and promoting recovery of disease-free stasis. The anti-inflammatory role of DFMO highlights the injurious effect of inflammation in gastric cancer development and the need to reduce gastric inflammation for cancer prevention. Conclusions: Overall, these mouse models provide reliable systems for analyzing the molecular mechanisms and synergistic effects of H. pylori and capsaicin on human cancer etiology. Accordingly, preventive measures like reduced capsaicin consumption, H. pylori clearance, and DFMO treatment can lessen gastric cancer incidence. Lastly, anti-inflammatory agents like DFMO can play important roles in prevention of inflammation-associated gastric cancer.

scholarly journals Current State of Preeclampsia Mouse Models: Approaches, Relevance, and Standardization

2021 ◽  
Vol 12 ◽  
Author(s):  
Christopher A. Waker ◽  
Melissa R. Kaufman ◽  
Thomas L. Brown
Keyword(s):  
Mouse Models ◽  
Molecular Mechanisms ◽  
Human Condition ◽  
Definitive Treatment ◽  
Specific Gene ◽  
Adenoviral Infection ◽  
Physiological Relevance ◽  
Increased Risk ◽  
Therapeutic Development ◽  
Surgical Manipulation

Preeclampsia (PE) is a multisystemic, pregnancy-specific disorder and a leading cause of maternal and fetal death. PE is also associated with an increased risk for chronic morbidities later in life for mother and offspring. Abnormal placentation or placental function has been well-established as central to the genesis of PE; yet much remains to be determined about the factors involved in the development of this condition. Despite decades of investigation and many clinical trials, the only definitive treatment is parturition. To better understand the condition and identify potential targets preclinically, many approaches to simulate PE in mice have been developed and include mixed mouse strain crosses, genetic overexpression and knockout, exogenous agent administration, surgical manipulation, systemic adenoviral infection, and trophoblast-specific gene transfer. These models have been useful to investigate how biological perturbations identified in human PE are involved in the generation of PE-like symptoms and have improved the understanding of the molecular mechanisms underpinning the human condition. However, these approaches were characterized by a wide variety of physiological endpoints, which can make it difficult to compare effects across models and many of these approaches have aspects that lack physiological relevance to this human disorder and may interfere with therapeutic development. This report provides a comprehensive review of mouse models that exhibit PE-like symptoms and a proposed standardization of physiological characteristics for analysis in murine models of PE.

Reaching the Threshold: A Multilayer Pathogenesis of Macrophage Activation Syndrome

2013 ◽  
Vol 40 (6) ◽  
pp. 761-767 ◽  
Author(s):  
Raffaele Strippoli ◽  
Ivan Caiello ◽  
Fabrizio De Benedetti
Keyword(s):  
Mouse Models ◽  
Inflammatory Cytokines ◽  
Genetic Background ◽  
Macrophage Activation Syndrome ◽  
Macrophage Activation ◽  
Molecular Mechanisms ◽  
Fatal Complication ◽  
Pathogenic Factors ◽  
Laboratory Features ◽  
Activation Syndrome

Macrophage activation syndrome (MAS) is a potentially fatal complication of rheumatic diseases. The condition is considered part of secondary hemophagocytic lymphohistiocytoses (HLH). There are similarities in genetic background, pathogenesis, and clinical and laboratory features with primary HLH (p-HLH). We describe findings in mouse models of secondary HLH, comparing them with models of p-HLH and the cellular and molecular mechanisms involved, and relate them to recent findings in patients with secondary HLH. A multilayer model is presented in which background inflammation, infections, and genetics all contribute in different proportions and in several ways. Once the “threshold” has been reached, inflammatory cytokines are the final effectors, independent of the interplay between different upstream pathogenic factors.

scholarly journals A20: a master regulator of arthritis

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Yongyao Wu ◽  
Xiaomin He ◽  
Ning Huang ◽  
Jiayun Yu ◽  
Bin Shao
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Mouse Models ◽  
Inflammatory Arthritis ◽  
Molecular Mechanisms ◽  
Related Research ◽  
Inflammatory Protein ◽  
New Findings ◽  
Tnf Α

Abstract A20, also known as TNF-α-induced protein 3 (TNFAIP3), is an anti-inflammatory protein that plays an important part in both immune responses and cell death. Impaired A20 function is associated with several human inflammatory and autoimmune diseases. Although the role of A20 in mediating inflammation has been frequently discussed, its intrinsic link to arthritis awaits further explanation. Here, we review new findings that further demonstrate the molecular mechanisms through which A20 regulates inflammatory arthritis, and we discuss the regulation of A20 by many factors. We conclude by reviewing the latest A20-associated mouse models that have been applied in related research because they reflect the characteristics of arthritis, the study of which will hopefully cast new light on anti-arthritis treatments.

scholarly journals Genetically Altered Mouse Models: the Good, the Bad, and the Ugly

2003 ◽  
Vol 14 (3) ◽  
pp. 154-174 ◽  
Author(s):  
Tamizchelvi Thyagarajan ◽  
Satish Totey ◽  
Mary Jo S. Danton ◽  
Ashok B. Kulkarni
Keyword(s):  
Gene Targeting ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Gene Knockout ◽  
Genetically Engineered ◽  
Murine Models ◽  
Functional Roles ◽  
Targeted Gene Disruption ◽  
Gene Knockout Mouse

Targeted gene disruption in mice is a powerful tool for generating murine models for human development and disease. While the human genome program has helped to generate numerous candidate genes, few genes have been characterized for their precise in vivo functions. Gene targeting has had an enormous impact on our ability to delineate the functional roles of these genes. Many gene knockout mouse models faithfully mimic the phenotypes of the human diseases. Because some models display an unexpected or no phenotype, controversy has arisen about the value of gene-targeting strategies. We argue in favor of gene-targeting strategies, provided they are used with caution, particularly in interpreting phenotypes in craniofacial and oral biology, where many genes have pleiotropic roles. The potential pitfalls are outweighed by the unique opportunities for developing and testing different therapeutic strategies before they are introduced into the clinic. In the future, we believe that genetically engineered animal models will be indispensable for gaining important insights into the molecular mechanisms underlying development, as well as disease pathogenesis, diagnosis, prevention, and treatment.

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