Advances In Mouse Models Research Articles

Advances in Mouse Models of Lupus

Systemic lupus erythematosus (SLE) is a typical autoimmune disease with complex clinical manifestations and involvement of organs and tissues of multiple systems throughout the body, but its pathogenesis is still unclear, therefore, the establishment of a suitable animal model of lupus is of great significance in exploring the etiology, pathogenesis and treatment of SLE. Constructing a lupus mouse model is a good tool for studying SLE. In this review, we will introduce the methods of establishing different kinds of lupus mouse models and their characteristics, and discuss the advantages and disadvantages of various models, with a view to providing researchers with references in the process of exploring the pathogenesis of lupus, and in the development of targeted interventions and therapeutic drugs.

Abstract 2839: The mouse models of human cancer database (MMHCdb)

Abstract The laboratory mouse plays a pivotal role as an experimental system for investigations into the genetic and genomic basis of cancer susceptibility, initiation, and progression and for preclinical research on novel treatment strategies for cancer. Advances in mouse models include humanized mice, transplant compliant mouse strains, and panels of genetically diverse mice (e.g., Diversity Outbred and Collaborative Cross). The distributed and heterogenous nature of information about these model systems presents a significant challenge to finding and aggregating information about mouse models and to identifying the most relevant models for a particular research question. The Mouse Models of Human Cancer database (http://tumor.informatics.jax.org) is an expertly curated FAIR-compliant knowledgebase that applies community annotation standards and nomenclature standards for genes, alleles, and strains to support accurate and comprehensive search results for mouse models of human cancer. The data in MMHCdb are curated from peer-reviewed scientific publications and direct data submissions from individual investigators and large-scale programs. A primary focus of the resource is to reflect the impact that genetic background has on the cancer-related characteristics of mouse models. The database includes information on spontaneous and genetically engineered cancer models as well as Patient Derived Xenografts and diversity panels. The database supports faceted searching for models by multiple criteria including, tumor type, genetic background of the mouse model, somatic mutations, and publication. Model descriptions include summaries of observed frequencies of tumors observed in the model and histopathology images. Information in MMHCdb is linked to cancer model data from other bioinformatics resources including the Patient Derived Cancer Models database (PDCM), PathBase, the Gene Expression Omnibus (GEO), and ArrayExpress. MMHCdb is supported by NCI R01 CA089713 Citation Format: Dale A. Begley, Debra M. Krupke, Emily Jocoy, Steven B. Neuhauser, Carol J. Bult. The mouse models of human cancer database (MMHCdb) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2839.

Mouse Models to Evaluate the Functional Role of the Tumor Microenvironment in Cancer Progression and Therapy Responses.

The tumor microenvironment (TME) is a complex ecosystem of both cellular and noncellular components that functions to impact the evolution of cancer. Various aspects of the TME have been targeted for the control of cancer; however, TME composition is dynamic, with the overall abundance of immune cells, endothelial cells (ECs), fibroblasts, and extracellular matrix (ECM) as well as subsets of TME components changing at different stages of progression and in response to therapy. To effectively treat cancer, an understanding of the functional role of the TME is needed. Genetically engineered mouse models have enabled comprehensive insight into the complex interactions within the TME ecosystem that regulate disease progression. Here, we review recent advances in mouse models that have been employed to understand how the TME regulates cancer initiation, progression, metastasis, and response to therapy.

Advances in respiratory physiology in mouse models of experimental asthma.

Recent advances in mouse models of experimental asthma coupled with vast improvements in systems that assess respiratory physiology have considerably increased the accuracy and human relevance of the outputs from these studies. In fact, these models have become important pre-clinical testing platforms with proven value and their capacity to be rapidly adapted to interrogate emerging clinical concepts, including the recent discovery of different asthma phenotypes and endotypes, has accelerated the discovery of disease-causing mechanisms and increased our understanding of asthma pathogenesis and the associated effects on lung physiology. In this review, we discuss key distinctions in respiratory physiology between asthma and severe asthma, including the magnitude of airway hyperresponsiveness and recently discovered disease drivers that underpin this phenomenon such as structural changes, airway remodeling, airway smooth muscle hypertrophy, altered airway smooth muscle calcium signaling, and inflammation. We also explore state-of-the-art mouse lung function measurement techniques that accurately recapitulate the human scenario as well as recent advances in precision cut lung slices and cell culture systems. Furthermore, we consider how these techniques have been applied to recently developed mouse models of asthma, severe asthma, and asthma-chronic obstructive pulmonary disease overlap, to examine the effects of clinically relevant exposures (including ovalbumin, house dust mite antigen in the absence or presence of cigarette smoke, cockroach allergen, pollen, and respiratory microbes) and to increase our understanding of lung physiology in these diseases and identify new therapeutic targets. Lastly, we focus on recent studies that examine the effects of diet on asthma outcomes, including high fat diet and asthma, low iron diet during pregnancy and predisposition to asthma development in offspring, and environmental exposures on asthma outcomes. We conclude our review with a discussion of new clinical concepts in asthma and severe asthma that warrant investigation and how we could utilize mouse models and advanced lung physiology measurement systems to identify factors and mechanisms with potential for therapeutic targeting.

Recent Advances in Mouse Models of Sjögren's Syndrome

Sjögren's syndrome (SS) is a complex rheumatoid disease that mainly affects exocrine glands, resulting in xerostomia (dry mouth) and xerophthalmia (dry eye). SS is characterized by autoantibodies, infiltration into exocrine glands, and ectopic expression of MHC II molecules on glandular epithelial cells. In contrast to the well-characterized clinical and immunological features, the etiology and pathogenesis of SS remain largely unknown. Animal models are powerful research tools for elucidating the pathogenesis of human diseases. To date, many mouse models of SS, including induced models, in which disease is induced in mice, and genetic models, in which mice spontaneously develop SS-like disease, have been established. These mouse models have provided new insight into the pathogenesis of SS. In this review, we aim to provide a comprehensive overview of recent advances in the field of experimental SS.

Sex effects in pyelonephritis.

Urinary tract infections (UTIs) are generally considered a disease of women. However, UTIs affect females throughout the lifespan, and certain male populations (including infants and elderly men) are also susceptible. Epidemiologically, pyelonephritis is more common in women but carries increased morbidity when it does occur in men. Among children, high-grade vesicoureteral reflux is a primary risk factor for upper-tract UTI in both sexes. However, among young infants with UTI, girls are outnumbered by boys; risk factors include posterior urethral valves and lack of circumcision. Recent advances in mouse models of UTI reveal sex differences in innate responses to UTI, which vary somewhat depending on the system used. Moreover, male mice and androgenized female mice suffer worse outcomes in experimental pyelonephritis; evidence suggests that androgen exposure may suppress innate control of infection in the urinary tract, but additional androgen effects, as well as non-hormonal sex effects, may yet be specified. Among other intriguing directions, recent experiments raise the hypothesis that the postnatal testosterone surge that occurs in male infants may represent an additional factor driving the higher incidence of UTI in males under 6months of age. Ongoing work in contemporary models will further illuminate sex- and sex-hormone-specific effects on UTI pathogenesis and immune responses.

Meningeal Mast Cells as Key Effectors of Stroke Pathology.

Stroke is the leading cause of adult disability in the United States. Because post-stroke inflammation is a critical determinant of damage and recovery after stroke, understanding the interplay between the immune system and the brain after stroke holds much promise for therapeutic intervention. An understudied, but important aspect of this interplay is the role of meninges that surround the brain. All blood vessels travel through the meningeal space before entering the brain parenchyma, making the meninges ideally located to act as an immune gatekeeper for the underlying parenchyma. Emerging evidence suggests that the actions of immune cells resident in the meninges are essential for executing this gatekeeper function. Mast cells (MCs), best known as proinflammatory effector cells, are one of the long-term resident immune cells in the meninges. Here, we discuss recent findings in the literature regarding the role of MCs located in the meningeal space and stroke pathology. We review the latest advances in mouse models to investigate the roles of MCs and MC-derived products in vivo, and the importance of using these mouse models. We examine the concept of the meninges playing a critical role in brain and immune interactions, reevaluate the perspectives on the key effectors of stroke pathology, and discuss the opportunities and challenges for therapeutic development.

Recent advances in mouse models for systemic sclerosis

SSc is a complex rheumatoid disease characterized by autoimmunity, fibrosis and vasculopathy. Mouse models provide powerful research tools for exploring the pathogenesis of the human diseases. Each mouse model can represent a specific way leading to the development of disease. Moreover, mouse models can be used to investigate the role of candidate molecule in the pathogenesis of disease. So far, more than twenty mouse models for SSc have been established and provide new insights in the understanding of the pathogenesis of SSc. In this review, we provide an overview on recent advances in the field of experimental SSc. We introduce novel mouse models generated in the recent years and discuss their relevance to the SSc pathogenesis. Moreover, we summarize and discuss recent findings in the pathogenesis of classical SSc mouse models.

Abstract LB-006: Oncology model fidelity scores

Abstract Animal models remain a cornerstone of research efforts in Oncology to model the complexity of cancer progression and to discover new therapeutic approaches to disease management. With the advent of new genomic manipulation techniques such as CRISPR, and advances in mouse modeling with genetically engineered mice (GEM) and patient-derived xenografts (PDX), we can expect the development of novel and powerful animal models in the near future. These techniques are expanding our capability for pre-clinical testing of novel therapeutic agents or for n-of-1 patient-specific disease modeling. However, the reliability of animal models to faithfully recapitulate human disease, especially cancer, remains controversial, as evidenced by numerous therapeutic agents that show promise in animal models but fail in clinical trials. We propose a new scoring system called the Oncology Model Fidelity Scores, which allow researchers and clinicians to compare animal models and select those most suited for the question at hand, whether in basic science, for translational research, or within clinical applications. The formalism and tools we are developing for the analysis of mouse models and other model organisms are based on the Hallmarks of Cancer and therapeutic pathways as well as The Cancer Genome Atlas (TCGA) and other comprehensive systems. The scoring system begins with RNASEQ expression data and DNA variation analysis, and is designed for use in mapping animal models both to individual patients and to a TCGA cohort. We are applying this scoring system to mouse models available through NCI’s Oncology Model Forum and we are analyzing how these animal models compare to human cancers based on TCGA data. Ultimately, the development of an Oncology Model Fidelity Score will help to advance patient care through efficient identification and validation of animal models for a variety of applications, from pre-clinical testing of novel therapeutics to the use of patient-specific animal models. Citation Format: Debajyoti Datta, Theodore Goldstein, Zhiping Gu, Atul Butte. Oncology model fidelity scores [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-006. doi:10.1158/1538-7445.AM2017-LB-006

Advances in Mouse Models of Sjögren's Syndrome.

Sjögren's syndrome (SS) is a common chronic systemic autoimmune disease;however,its pathogenic mechanisms remain unclear. Proper mouse models of SS are essential for experiments. This article summarizes the recent advances in spontaneous mouse models of SS,genetically engineered mouse models of SS,and experimentally induced mouse models of SS.

Applying humanized mouse models to immune therapy research

Mouse models have been a mainstay in biomedical research for decades. As these models have become more sophisticated, their application has grown and now includes a wide variety of immunodeficient strains that can be used to examine the in vivo growth of human tumors and to test new cancer treatments. One of the most popular models is the immunodeficient nonobese diabetic severe combined immunodeficiency (NOD scid) gamma (NSG) transgenic mouse line, which can be endowed with a humanized immune system using CD34+ hematopoietic stem cells. Next-generation NSG models that support human myeloid cell proliferation, such as the NSG-SGM3 mouse, can now provide in vivo conditions that better mimic the natural tumor environment. Human tumor tissue or cell lines can be coengrafted into these mouse models, providing a powerful tool for studying the interactions between human immune cells and human cancers. In this webinar we will discuss the latest advances in mouse models for cancer research and how they are being applied to help us understand the pathways and mechanisms involved in new immune therapies.

Tissue Recombination Models for the Study of Epithelial Cancer.

Animal models of cancer provide fundamental insight into the cellular and molecular mechanisms of human cancer development. As an alternative to genetically engineered mouse models, increasing evidence shows that tissue recombination and transplantation models represent an efficient approach to faithfully recapitulate solid epithelial cancer in mice. Cancer can be rapidly initiated through lentiviral delivery of defined genetic alterations into target cells that are grown in a physiological milieu with an appropriate epithelial-stromal interaction. Through genetic manipulation of distinct subpopulations of epithelial cells and mesenchymal cells, this powerful system can readily test both cell-autonomous roles of genetic events in the epithelial compartment and the paracrine effects of the microenvironment. Here we review the recent advances in mouse models of several epithelial cancers achieved using orthotopic transplantation and tissue recombination strategies, with an emphasis on the dissociated cell in vivo prostate regeneration model to investigate prostate cancer.

Viral-mediated Labeling and Transplantation of Medial Ganglionic Eminence (MGE) Cells for In Vivo Studies.

GABAergic cortical interneurons, derived from the embryonic medial and caudal ganglionic eminences (MGE and CGE), are functionally and morphologically diverse. Inroads have been made in understanding the roles of distinct cortical interneuron subgroups, however, there are still many mechanisms to be worked out that may contribute to the development and maturation of different types of GABAergic cells. Moreover, altered GABAergic signaling may contribute to phenotypes of autism, schizophrenia and epilepsy. Specific Cre-driver lines have begun to parcel out the functions of unique interneuron subgroups. Despite the advances in mouse models, it is often difficult to efficiently study GABAergic cortical interneuron progenitors with molecular approaches in vivo. One important technique used to study the cell autonomous programming of these cells is transplantation of MGE cells into host cortices. These transplanted cells migrate extensively, differentiate, and functionally integrate. In addition, MGE cells can be efficiently transduced with lentivirus immediately prior to transplantation, allowing for a multitude of molecular approaches. Here we detail a protocol to efficiently transduce MGE cells before transplantation for in vivo analysis, using available Cre-driver lines and Cre-dependent expression vectors. This approach is advantageous because it combines precise genetic manipulation with the ability of these cells to disperse after transplantation, permitting greater cell-type specific resolution in vivo.

Recent advances in mouse models of obesity- and nonalcoholic steatohepatitis-associated hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is the fifth most common cancer, and obesity has been established as a risk factor for HCC development. Nonalcoholic steatohepatitis (NASH) is apparently the key link between obesity and hepatocarcinogenesis, and obesity also accelerates HCC development synergistically with other risk factors, such as hepatitis virus infection and alcohol consumption. As an explanation for the pathogenesis of NASH, the so-called "two-hit" theory has been widely accepted, but recently, a better model, the so-called "multiple-hits hypothesis" was proposed, which states that many disease-promoting factors may occur in parallel, rather than consecutively. However, the overall mechanism remains largely unknown. Various cell-cell and organ-organ interactions are involved in the pathogenesis of NASH, and thus appropriate in vivo disease models are essential for a deeper understanding. However, replicating the full spectrum of human NASH has been difficult, as NASH involves obesity, insulin resistance, steatohepatitis, fibrosis, and ultimately HCC, and the lack of an appropriate mouse model has been a considerable barrier to determining the missing links among obesity, NASH, and HCC. In recent years, several innovative mouse models presenting obesity- and NASH-associated HCC have been established by modified diets, chemotoxic agents, genetic manipulation, or a combination of these factors, shedding some light on this complex network and providing new therapeutic strategies. Thus, in this paper, I review the mouse models of obesity- and NASH-associated HCC, especially focusing on recent advances and their clinical relevance.

Dual Face of Immune Microenvironment in Myeloma

An important property of human multiple myeloma (MM) is the growth of tumor cells and their precursors in the bone marrow microenvironment. This specialized microenvironment includes a distinct component of immune cells that includes cells of innate as well as adaptive immune system. Growing body of evidence points to a central role for cross-talk between this immune microenvironment and tumor cells in regulating the growth of tumor cells in myeloma. These interactions play a dual role-with some interactions promoting tumor growth while others suppress growth of tumor cells. Cross talk between T and B cells has been implicated in normal B/plasma cell differentiation and may also play a role in pathogenesis of myeloma, explaining increased risk of plasma cell malignancies in certain settings such as Gaucher disease. The bone marrow of MM patients is often infiltrated with innate cells such as dendritic cells (DCs) and cross-talk between myeloid/plasmacytoid DCs or macrophages may promote growth and survival of MM cells. This cross-talk may also have fundamental implications for inducing genomic instability in tumor cells, such as via the induction of cytidine deaminases in tumor cells. Genomic instability is an early feature of human MM and many of the mutations found in MM tumor cells are also present in the precursor states. The immune system has the capacity to recognize these precursor lesions and even in the setting of clinical MM, the tumor bed contains T cells that can be recruited to kill tumor cells. Specific targets of tumor immunity may differ between preclinical and clinical malignancy. Immunity to certain stem cell-associated antigens are in particular associated with reduced risk of progression to clinical MM. With advanced disease, tumor infiltrating T cells encounter several immune inhibitory checkpoints which leads to suppression of function of tumor-infiltrating T cells. In addition to T cells, cells of the innate immune system such as natural killer and natural killer T cells may also be attractive targets of protective tumor immunity in MM. Immunologic approaches may also be combined with other strategies such as other immunomodulatory drugs (IMiDs) already in clinical use in MM. Recent advances in mouse modeling provide new opportunities to better understand how to harness the immune system against human MM. Such approaches have the advantage of the potential for durable control of tumor cells via immunologic memory. Such approaches are now entering the clinic as attractive targets to restore anti-tumor immunity, both in the context of therapy or prevention of MM. Disclosures Dhodapkar: Celgene: Research Funding. Off Label Use: checkpoint blockade drugs, imids.

Challenges and advances in mouse modeling for human pancreatic tumorigenesis and metastasis.

Pancreatic cancer is critical for developed countries, where its rate of diagnosis has been increasing steadily annually. In the past decade, the advances of pancreatic cancer research have not contributed to the decline in mortality rates from pancreatic cancer-the overall 5-year survival rate remains about 5% low. This number only underscores an obvious urgency for us to better understand the biological features of pancreatic carcinogenesis, to develop early detection methods, and to improve novel therapeutic treatments. To achieve these goals, animal modeling that faithfully recapitulates the whole process of human pancreatic cancer is central to making the advancements. In this review, we summarize the currently available animal models for pancreatic cancer and the advances in pancreatic cancer animal modeling. We compare and contrast the advantages and disadvantages of three major categories of these models: (1) carcinogen-induced; (2) xenograft and allograft; and (3) genetically engineered mouse models. We focus more on the genetically engineered mouse models, a category which has been rapidly expanded recently for their capacities to mimic human pancreatic cancer and metastasis, and highlight the combinations of these models with various newly developed strategies and cell-lineage labeling systems.

Modeling and predicting clinical efficacy for drugs targeting the tumor milieu

Disappointing results from most late-stage clinical trials of cancer therapeutics indicate a need for improved and more-predictive animal tumor models. This insufficiency of models, combined with the advent of a class of drugs that target the tumor microenvironment rather than the tumor cell, presents new challenges for designing and interpreting preclinical efficacy studies. A comparison of the clinical efficacy of anti-angiogenic drugs with their corresponding preclinical studies over the past two decades offers many lessons that can inform and improve the design of experiments in existing mouse models. In addition, technological and logistical advances in mouse models of human cancer over the past five years have the potential to increase the clinical translatability of animal studies.

Advances in comparative genetics: influence of genetics on obesity

Obesity has reached epidemic proportions and is recognised as a significant global health problem. Increased food intake and decreased physical activity are traditionally to blame for the development of obesity; however, many variables such as behaviour, diet, environment, social structures and genetics also contribute to this multifactorial disease. Complex interactions among these variables (for example, gene-environment, gene-diet and gene-gene) contribute not only to individual differences in the development of obesity, but also in treatment response. Mouse models have historically played valuable roles in understanding the genetics of traits related to energy balance and obesity. In the present review, we survey past use and examine new advances in mouse models designed to uncover the genetic architecture of obesity and its component traits. We discuss traditional models such as inbred strains and selectively bred lines and their contributions and shortcomings. We consider the evolution of mouse models into more informative resources such as outbred crosses and the Hybrid Mouse Diversity Panel, as well as novel next-generation approaches such as the Collaborative Cross. Moreover, the genetic architecture of voluntary exercise and the interactive relationship between host genetics and the gut microbiome are presented as novel phenotypes that augment studies using body weight and body fat percentage as endpoints. Understanding the intricate network of phenotypic, genotypic and environmental variables that predispose individuals to obesity will elucidate biological networks involved in the development of obesity. Knowledge obtained from advances in mouse models will inform human health and provide insight into inter-individual variability in the aetiology of obesity-related diseases.

Molecular genetics of optic glioma: lessons learned from neurofibromatosis-1 genetically engineered mice

Neurofibromatosis type 1 is an inherited cancer predisposition syndrome in which 15–20% of children develop optic gliomas. Most of these tumors form along the optic nerve and chiasm, where they can cause decreased visual function and endocrine dysfunction. Advances in mouse modeling of this disease have created tractable models to study the role of specific genetic alterations, deregulated intracellular signaling pathways and non-neoplastic cells in the development of optic gliomas. These small-animal models have been used as platforms to discover new targets for drug design and to evaluate the efficacy of these potential anticancer treatments prior to clinical trials in children with optic glioma.

Ras-Induced Senescence and its Physiological Relevance in Cancer

Activated oncogenes like Ras have traditionally been thought as promoting unrestrained proliferation; therefore, the concept of oncogene-induced senescence has been, and still is, controversial. The counter-intuitive notion that activation of oncogenes leads to the prevention of cellular proliferation has initially been fueled by in vitro studies using ectopic expression of activated Ras in primary fibroblasts. While these initial studies demonstrated unambiguously the existence of a new type of cellular senescence, induced by oncogenes in an ex-vivo system, questions were raised about the physiological relevance of this process. Indeed, recent technical advances in mouse modeling for cancer have suggested that the occurrence of Ras-induced senescence is highly dependent on the cellular context, as well as the level of expression of activated Ras, and may not be pertinent to the study of human cancer initiation and/or progression. However, our increased knowledge of the molecular basis for cellular senescence has led to a better understanding of the molecular events modulating cancer progression in vivo. Recent studies have not only clearly established the incidence of cellular senescence in pre-neoplasic lesions, but also its role as a potential tumor-suppressor mechanism in vivo. Here, we review the recent and exciting new findings regarding the physiological relevance of Ras-induced senescence, and discuss their implications in terms of cancer therapy.