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Models that have been used in the Zon lab. Key attributes of different animal models used for the study of human diseases are highlighted.
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Traditionally, most investigators in the biomedical arena exploit one model system in the course of their careers. Occasionally, an investigator will switch models. The selection of a suitable model system is a crucial step in research design. Factors to consider include the accuracy of the model as a reflection of the human disease under investiga...
Citations
... The biomedical research arena is undergoing a pivotal change in favor of human disease models such as organoids [1,2]. This change has been determined by the well-known high failure rates of the drug development process where animal models have been predominant (figure 1). ...
High failure rates of the current drug development process are driving exemplary changes toward methodologies centered on human disease in-vitro modeling. Organoids are self-organized tissue sub-units resembling their organ of origin and are widely acknowledged for their unique potential in recapitulating human physio-pathological mechanisms. They are transformative for human health by becoming the platform of choice to probe disease mechanisms and advance new therapies. Furthermore, the compounds’ validation as therapeutics represents another point of the drug development pipeline where organoids may provide key understandings and help pharma organizations replace or reduce animal research. In this review, we focus on gastrointestinal organoid models, which are currently the most advanced organoid models in drug development. We focus on experimental validations of their value, and we propose avenues to enhance their use in drug discovery and development, as well as precision medicine and diagnostics.
... In the field of developmental biology, these model facilitate the study of processes such as embryogenesis (Mummery et al., 2011), evolution (Sommer, 2009), aging (Sachs andBuchholz, 2017), tissue regeneration (Brockes and Kumar, 2008;Banerjee, 2014), and metamorphosis (Sachs and Buchholz, 2017). Also, these models are very important in biomedical research because they help to elucidate the molecular pathways that are involved in human diseases, allowing the testing of different substances in vivo (Zon, 2016) to discover new therapeutic strategies in the treatment of complex diseases such as cancer (Sachs and Buchholz, 2017), cardiovascular (Zaragoza et al., 2011), and degenerative diseases (Sachs and Buchholz, 2017). ...
Ambystoma mexicanum is a urodele amphibian endemic to Xochimilco Lake in Mexico, it belongs to the salamander family Ambystomatidae. This species has frequently been used as model organism in developmental biology and regeneration laboratories around the world due to its broad regenerative capacities and adaptability to laboratory conditions. In this review we describe the establishment of the first colony of axolotls in Colombia to study tissue regeneration and our perspectives on the use A. mexicanum as a model organism in Colombia are discussed emphasizing its possible uses in regeneration and developmental biology
... To learn about host-pathogen interactions during infection, one must have a good model. Researchers must consider how closely the model reflects human disease, the number of replicates needed, the ease of use, and the ability to manipulate the genetics of the model (175). In this section, I will review the characteristics, advantages and disadvantages of in vitro and in vivo models that have traditionally been used to study candidiasis. ...
Candida yeasts are common commensals that can cause mucosal disease and life-threatening systemic infections. While many of the components required for defense against Candida albicans infection are well established, questions remain about how various host cells at mucosal sites assess threats and coordinate defenses to prevent normally commensal organisms from becoming pathogenic. Using two Candida species, C. albicans and C. parapsilosis, which differ in their abilities to damage epithelial tissues, we used traditional methods (pathogen CFU, host survival, and host cytokine expression) combined with high-resolution intravital imaging of transparent zebrafish larvae to illuminate host-pathogen interactions at the cellular level in the complex environment of a mucosal infection. In zebrafish, C. albicans grows as both yeast and epithelium-damaging filaments, activates the NF-kB pathway, evokes proinflammatory cytokines, and causes the recruitment of phagocytic immune cells. On the other hand, C. parapsilosis remains in yeast morphology and elicits the recruitment of phagocytes without inducing inflammation. High-resolution mapping of phagocyte-Candida interactions at the infection site revealed that neutrophils and macrophages attack both Candida species, regardless of the cytokine environment. Time-lapse monitoring of single-cell gene expression in transgenic reporter zebrafish revealed a partitioning of the immune response during C. albicans infection: the transcription factor NF-kB is activated largely in cells of the swimbladder epithelium, while the proinflammatory cytokine tumor necrosis factor alpha (TNF-a) is expressed in motile cells, mainly macrophages. Our results point to different host strategies for combatting pathogenic Candida species and separate signaling roles for host cell types.
... For example, outcomes such as "cognition," "behavior," and "anxiety" may rely on very different paradigms in animals in comparison with humans. However, to successfully translate basic science discoveries into clinical practice, investigators benefit from considering a range of models and collaborations with other investigators and the medical community to ensure clinical relevance of outcomes and facilitate translation of basic science findings to the clinic (Zon, 2016). ...
... Animal models are fundamental tools in biomedical research because they can fill the gap between basic science and the treatment of human diseases (Zon, 2016). Several different animal models can be used to study the gene function providing new insight into pathophysiology of human disorders (Bier and McGinnis, 2004). ...
Hematopoiesis results in the correct formation of all the different blood cell types. In mammals, it starts from specific hematopoietic stem and precursor cells residing in the bone marrow. Mature blood cells are responsible for supplying oxygen to every cell of the organism and for the protection against pathogens. Therefore, inherited or de novo genetic mutations affecting blood cell formation or the regulation of their activity are responsible for numerous diseases including anemia, immunodeficiency, autoimmunity, hyper- or hypo-inflammation, and cancer. By definition, an animal disease model is an analogous version of a specific clinical condition developed by researchers to gain information about its pathophysiology. Among all the model species used in comparative medicine, mice continue to be the most common and accepted model for biomedical research. However, because of the complexity of human diseases and the intrinsic differences between humans and other species, the use of several models (possibly in distinct species) can often be more helpful and informative than the use of a single model. In recent decades, the zebrafish (Danio rerio) has become increasingly popular among researchers, because it represents an inexpensive alternative compared to mammalian models, such as mice. Numerous advantages make it an excellent animal model to be used in genetic studies and in particular in modeling human blood diseases. Comparing zebrafish hematopoiesis to mammals, it is highly conserved with few, significant differences. In addition, the zebrafish model has a high-quality, complete genomic sequence available that shows a high level of evolutionary conservation with the human genome, empowering genetic and genomic approaches. Moreover, the external fertilization, the high fecundity and the transparency of their embryos facilitate rapid, in vivo analysis of phenotypes. In addition, the ability to manipulate its genome using the last genome editing technologies, provides powerful tools for developing new disease models and understanding the pathophysiology of human disorders. This review provides an overview of the different approaches and techniques that can be used to model genetic diseases in zebrafish, discussing how this animal model has contributed to the understanding of genetic diseases, with a specific focus on the blood disorders.
... This latter feature is important for establishing functional significance, as well as for evaluating drug metabolism and toxicity. Higher-order models can serve as a critical segue between preliminary investigations performed in simpler organisms, such as yeast, and more definitive validation in murine models and eventually humans (Zon 2016). ...
Genetic diseases are both inherited and acquired. Many genetic diseases fall under the paradigm of orphan diseases, a disease found in < 1 in 2000 persons. With rapid and cost-effective genome sequencing becoming the norm, many causal mutations for genetic diseases are being rapidly determined. In this regard, model organisms are playing an important role in validating if specific mutations identified in patients drive the observed phenotype. An emerging challenge for model organism researchers is the application of genetic and chemical genetic platforms to discover drug targets and drugs/drug-like molecules for potential treatment options for patients with genetic disease. This review provides an overview of how model organisms have contributed to our understanding of genetic disease, with a focus on the roles of yeast and zebrafish in gene discovery and the identification of compounds that could potentially treat human genetic diseases.
... This may help us to identify other potential functions and interacting partners for this family of proteins. Zebrafish is a powerful model system for elucidating developmental and cell biological processes and for modeling and studying human diseases (e.g., Hostetter et al., 2003;Huang et al., 2014;Avagyan and Zon, 2016;Bournele and Beis, 2016;Brown et al., 2016;Carneiro et al., 2016;Griffin et al., 2016;Harrison et al., 2016;Kozol et al., 2016;Myllymaki et al., 2016;Poureetezadi and Wingert, 2016;Song et al., 2016;Wager et al., 2016;Wojciechowska et al., 2016;Zon, 2016). Consistent with this, all of the evidence so far suggests that zebrafish pkd genes function in ways that are highly conserved with their mammalian orthologs. ...
Polycystic kidney disease (PKD) proteins are trans-membrane proteins that have crucial roles in many aspects of vertebrate development and physiology, including the development of many organs as well as left–right patterning and taste. They can be divided into structurally-distinct PKD1-like and PKD2-like proteins and usually one PKD1-like protein forms a heteromeric polycystin complex with a PKD2-like protein. For example, PKD1 forms a complex with PKD2 and mutations in either of these proteins cause Autosomal Dominant Polycystic Kidney Disease (ADPKD), which is the most frequent potentially-lethal single-gene disorder in humans. Here, we identify the complete family of pkd genes in zebrafish and other teleosts. We describe the genomic locations and sequences of all seven genes: pkd1, pkd1b, pkd1l1, pkd1l2a, pkd1l2b, pkd2, and pkd2l1. pkd1l2a/pkd1l2b are likely to be ohnologs of pkd1l2, preserved from the whole genome duplication that occurred at the base of the teleosts. However, in contrast to mammals and cartilaginous and holostei fish, teleosts lack pkd2l2, and pkdrej genes, suggesting that these have been lost in the teleost lineage. In addition, teleost, and holostei fish have only a partial pkd1l3 sequence, suggesting that this gene may be in the process of being lost in the ray-finned fish lineage. We also provide the first comprehensive description of the expression of zebrafish pkd genes during development. In most structures we detect expression of one pkd1-like gene and one pkd2-like gene, consistent with these genes encoding a heteromeric protein complex. For example, we found that pkd2 and pkd1l1 are expressed in Kupffer's vesicle and pkd1 and pkd2 are expressed in the developing pronephros. In the spinal cord, we show that pkd1l2a and pkd2l1 are co-expressed in KA cells. We also identify potential co-expression of pkd1b and pkd2 in the floor-plate. Interestingly, and in contrast to mouse, we observe expression of all seven pkd genes in regions that may correspond to taste receptors. Taken together, these results provide a crucial catalog of pkd genes in an important model system for elucidating cell and developmental processes and modeling human diseases and the most comprehensive analysis of embryonic pkd gene expression in any vertebrate.
Zebrafish are widely used as a model organism for research. Zebrafish embryos are also a useful resource for teaching students about vertebrate development. Here we describe a collaboration between two high school teachers and two university professors that used zebrafish to bring hands-on laboratory experiences to inner-city students, with the aim of increasing tangibility, and improving student understanding and retention, of several fundamental scientific concepts, such as the scientific method, cell division, mitosis, and Mendelian genetics. We describe and provide supporting material for each of the four laboratory modules that we developed. We also discuss the obstacles that we encountered and include suggestions of ways to overcome these. This collaboration provides an example of how high school teachers with very little zebrafish experience can gain the knowledge and confidence to develop and implement modules such as these in a relatively short period of time. Owing to the wide availability of zebrafish resources, these laboratories should provide a useful resource for other teachers who are interested in integrating more hands-on, inquiry-based investigations using live animals into their classes. We also hope to encourage other zebrafish researchers to collaborate with local teachers in similar projects.
