Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Animal Model Contributions to Congenital Metabolic Disease.

ABSTRACT: Genetic model systems allow researchers to probe and decipher aspects of human disease, and animal models of disease are frequently specifically engineered and have been identified serendipitously as well. Animal models are useful for probing the etiology and pathophysiology of disease and are critical for effective discovery and development of novel therapeutics for rare diseases. Here we review the impact of animal model organism research in three examples of congenital metabolic disorders to highlight distinct advantages of model system research. First, we discuss phenylketonuria research where a wide variety of research fields and models came together to make impressive progress and where a nearly ideal mouse model has been central to therapeutic advancements. Second, we review advancements in Lesch-Nyhan syndrome research to illustrate the role of models that do not perfectly recapitulate human disease as well as the need for multiple models of the same disease to fully investigate human disease aspects. Finally, we highlight research on the GM2 gangliosidoses Tay-Sachs and Sandhoff disease to illustrate the important role of both engineered traditional laboratory animal models and serendipitously identified atypical models in congenital metabolic disorder research. We close with perspectives for the future for animal model research in congenital metabolic disorders.

SUBMITTER: Moro CA

PROVIDER: S-EPMC8404832 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Animal model of Crohn’s disease

Project description:Dysbiosis of the fecal microbiota in the TNBS-induced Crohn’s disease mouse model

| PRJEB10309 | ENA

NK2 model of congenital heart disease

Project description:Lack of the conserved NK2-domain of the cardiac transcription factor Nkx2.5 causes multiple heart defects . The NK2 family of homeobox genes constitutes a family of transcription factors that play an important role in different developmental processes. Members of this group are characterized by two highly conserved protein domains: the homeodomain, conferring DNA binding activity, and the NK2-specific domain (NK2-SD) of yet unknown function. One of the best characterized members of this group is the early cardiogenic marker Nkx2.5. Loss of function of Nkx2.5 leads to embryonic lethality around E10.5 due to an arrest of heart development at the looping stage. We have further dissected the function of Nkx2.5 in vivo by creating a knockout mouse line harboring an in frame deletion of the NK2-SD by Cre/loxP mediated excision. Homozygous mutant mice die at E14.5 due to severe cardiac malformations, e.g. common AV canal, DORV, and VSD. Lack of the NK2-SD leads to downregulation of the ventricular markers MLC-2v and Irx4 specifically in the right ventricle, and is accompanied with reduced right ventricular function. This function of Nkx2.5 seems to be independent of its ability to bind target DNA, since lack of the NK2-SD does not alter the DNA binding activity of Csx/Nkx2.5 in vitro. Heterozygous mutant mice show a spectrum of cardiac defects related to cardiac septation and valve morphogenesis, but lack conduction system defects as reported for heterozygous Nkx2.5 mice. The phenotype observed in NK2-SD mutant mice shows that Nkx2.5 is not only crucial during early steps of cardiogenesis but also plays an important role at later developmental stages. Embryos were isolated at embryonic day 12.5. The entire embryo heart was taken and isolated in ice-cold PBS and immediately frozen on dry-ice. Total RNA was extracted from pooled samples of wildtype, heterozygous and mutant embryos. Keywords = congenital heart disease, Csx, Nkx2.5 Keywords: other

2003-07-13 | GSE528 | GEO

Human filariasis-contributions of the Litomosoides sigmodontis and Acanthocheilonema viteae animal model.

Project description:Filariae are vector-borne parasitic nematodes that are endemic worldwide, in tropical and subtropical regions. Important human filariae spp. include Onchocerca volvulus, Wuchereria bancrofti and Brugia spp., and Loa loa and Mansonella spp. causing onchocerciasis (river blindness), lymphatic filariasis (lymphedema and hydrocele), loiasis (eye worm), and mansonelliasis, respectively. It is estimated that over 1 billion individuals live in endemic regions where filarial diseases are a public health concern contributing to significant disability adjusted life years (DALYs). Thus, efforts to control and eliminate filarial diseases were already launched by the WHO in the 1970s, especially against lymphatic filariasis and onchocerciasis, and are mainly based on mass drug administration (MDA) of microfilaricidal drugs (ivermectin, diethylcarbamazine, albendazole) to filarial endemic areas accompanied with vector control strategies with the goal to reduce the transmission. With the United Nations Sustainable Development Goals (SDGs), it was decided to eliminate transmission of onchocerciasis and stop lymphatic filariasis as a public health problem by 2030. It was also requested that novel drugs and treatment strategies be developed. Mouse models provide an important platform for anti-filarial drug research in a preclinical setting. This review presents an overview about the Litomosoides sigmodontis and Acanthocheilonema viteae filarial mouse models and their role in immunological research as well as preclinical studies about novel anti-filarial drugs and treatment strategies.

| S-EPMC8599372 | biostudies-literature

Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease.

Project description:Hereditary tyrosinemia type I (HT1) is caused by deficiency in fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the last step of tyrosine metabolism. The most severe form of the disease presents acutely during infancy, and is characterized by severe liver involvement, most commonly resulting in death if untreated. Generation of FAH(+/-) pigs was previously accomplished by adeno-associated virus-mediated gene knockout in fibroblasts and somatic cell nuclear transfer. Subsequently, these animals were outbred and crossed to produce the first FAH(-/-) pigs. FAH-deficiency produced a lethal defect in utero that was corrected by administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3 cyclohexanedione (NTBC) throughout pregnancy. Animals on NTBC were phenotypically normal at birth; however, the animals were euthanized approximately four weeks after withdrawal of NTBC due to clinical decline and physical examination findings of severe liver injury and encephalopathy consistent with acute liver failure. Biochemical and histological analyses, characterized by diffuse and severe hepatocellular damage, confirmed the diagnosis of severe liver injury. FAH(-/-) pigs provide the first genetically engineered large animal model of a metabolic liver disorder. Future applications of FAH(-/-) pigs include discovery research as a large animal model of HT1 and spontaneous acute liver failure, and preclinical testing of the efficacy of liver cell therapies, including transplantation of hepatocytes, liver stem cells, and pluripotent stem cell-derived hepatocytes.

| S-EPMC4096906 | biostudies-literature

Metabolic Syndrome in Adults With Congenital Heart Disease.

Project description:Metabolic syndrome increases risk for atherosclerotic coronary artery disease, and its prevalence increases with increasing age and body mass index. Adults with congenital heart disease (ACHD) are now living longer and accruing coronary artery disease risk factors. However, the prevalence of metabolic syndrome in ACHD patients is unknown.We conducted a retrospective cohort study of ACHD patients at our center to quantify the prevalence of metabolic syndrome in an ACHD population. Using case-control matching, we constructed a comparable control group from a population-based sample of 150 104 adults. International Diabetes Federation criteria were used to define metabolic syndrome. We used logistic regression to compare the risk of metabolic syndrome across the resulting cohorts, which were composed of 448 ACHD patients and 448 controls matched by age and sex. Mean age of both groups was 32.4±11.3 years, and 51.3% were female. Obesity was present in 16.1% of the ACHD patients and 16.7% of the controls. Metabolic syndrome was more common in ACHD patients than in controls (15.0% versus 7.4%; odds ratio 1.82, 95% CI 1.25-2.65).Our data suggest that metabolic syndrome is more common among adults with congenital heart disease than in the general population. Thus, patients with congenital heart disease should be screened for metabolic syndrome and risk factors mitigated where possible to prevent atherosclerotic coronary artery disease. Preventive cardiology should be included during routine ACHD care.

| S-EPMC4802435 | biostudies-other

Novel animal model defines genetic contributions for neuron-to-neuron transfer of ?-synuclein.

Project description:Cell-to-cell spreading of misfolded ?-synuclein (?-syn) is suggested to contribute to the progression of neuropathology in Parkinson's disease (PD). Compelling evidence supports the hypothesis that misfolded ?-syn transmits from neuron-to-neuron and seeds aggregation of the protein in the recipient cells. Furthermore, ?-syn frequently appears to propagate in the brains of PD patients following a stereotypic pattern consistent with progressive spreading along anatomical pathways. We have generated a C. elegans model that mirrors this progression and allows us to monitor ?-syn neuron-to-neuron transmission in a live animal over its lifespan. We found that modulation of autophagy or exo/endocytosis, affects ?-syn transfer. Furthermore, we demonstrate that silencing C. elegans orthologs of PD-related genes also increases the accumulation of ?-syn. This novel worm model is ideal for screening molecules and genes to identify those that modulate prion-like spreading of ?-syn in order to target novel strategies for disease modification in PD and other synucleinopathies.

| S-EPMC5548897 | biostudies-other

CrxRdy Cat: A Large Animal Model for CRX-Associated Leber Congenital Amaurosis.

Project description:PurposeMutations in the retinal transcription factor cone-rod homeobox (CRX) gene result in severe dominant retinopathies. A large animal model, the Rdy cat, carrying a spontaneous frameshift mutation in Crx, was reported previously. The present study aimed to further understand pathogenesis in this model by thoroughly characterizing the Rdy retina.MethodsStructural and functional changes were found in a comparison between the retinas of CrxRdy/+ kittens and those of wild-type littermates and were determined at various ages by fundus examination, electroretinography (ERG), optical coherence tomography, and histologic analyses. RNA and protein expression changes of Crx and key target genes were analyzed using quantitative reverse-transcribed PCR, Western blot analysis, and immunohistochemistry. Transcription activity of the mutant Crx was measured by a dual-luciferase transactivation assay.ResultsCrxRdy/+ kittens had no recordable cone ERGs. Rod responses were delayed in development and markedly reduced at young ages and lost by 20 weeks. Photoreceptor outer segment development was incomplete and was followed by progressive outer retinal thinning starting in the cone-rich area centralis. Expression of cone and rod Crx target genes was significantly down-regulated. The mutant Crx allele was overexpressed, leading to high levels of the mutant protein lacking transactivation activity.ConclusionsThe CrxRdy mutation exerts a dominant negative effect on wild-type Crx by overexpressing mutant protein. These findings, consistent with those of studies in a mouse model, support a conserved pathogenic mechanism for CRX frameshift mutations. The similarities between the feline eye and the human eye with the presence of a central region of high cone density makes the CrxRdy/+ cat a valuable model for preclinical testing of therapies for dominant CRX diseases.

| S-EPMC4960999 | biostudies-literature

Insights into the genetic architecture of congenital heart disease from animal modeling.

Project description:Congenital heart disease (CHD) is observed in up to 1% of live births and is one of the leading causes of mortality from birth defects. While hundreds of genes have been implicated in the genetic etiology of CHD, their role in CHD pathogenesis is still poorly understood. This is largely a reflection of the sporadic nature of CHD, as well as its variable expressivity and incomplete penetrance. We reviewed the monogenic causes and evidence for oligogenic etiology of CHD, as well as the role of de novo mutations, common variants, and genetic modifiers. For further mechanistic insight, we leveraged single-cell data across species to investigate the cellular expression characteristics of genes implicated in CHD in developing human and mouse embryonic hearts. Understanding the genetic etiology of CHD may enable the application of precision medicine and prenatal diagnosis, thereby facilitating early intervention to improve outcomes for patients with CHD.

| S-EPMC10236297 | biostudies-literature

Astrocytes Undergo Metabolic Reprogramming in the Multiple Sclerosis Animal Model.

Project description:Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that presents a largely unknown etiopathology. The presence of reactive astrocytes in MS lesions has been described for a long time; however, the role that these cells play in the pathophysiology of MS is still not fully understood. Recently, we used an MS animal model to perform high-throughput sequencing of astrocytes' transcriptome during disease progression. Our data show that astrocytes isolated from the cerebellum (a brain region typically affected in MS) showed a strong alteration in the genes that encode for proteins related to several metabolic pathways. Specifically, we found a significant increase in glycogen degradation, glycolytic, and TCA cycle enzymes. Together with these alterations, we detected an upregulation of genes that characterize "astrocyte reactivity". Additionally, at each disease time point we also reconstructed the morphology of cerebellum astrocytes in non-induced controls and in EAE animals, near lesion regions and in the normal-appearing white mater (NAWM). We found that near lesions, astrocytes presented increased length and complexity compared to control astrocytes, while no significant alterations were observed in the NAWM. How these metabolic alterations are linked with disease progression is yet to be uncovered. Herein, we bring to the literature the hypothesis of performing metabolic reprogramming as a novel therapeutic approach in MS.

| S-EPMC10605171 | biostudies-literature

Cortical stimulation-based transcriptome shifts on Parkinson's disease animal model

Project description:Parkinson's disease is the second most prevalent neurodegenerative disorder, characterized by the degeneration of dopaminergic neurons. Significant improvements in gait balance, particularly step length and velocity, were revealed by less-invasive wireless cortical stimulation. Transcriptome sequencing was performed to demonstrate the cellular mechanism, specifically targeting the primary motor cortex where the stimulation was applied. Our findings indicated that the differentially expressed genes (DEGs), initially down-regulated following Parkinson's disease induction, were subsequently restored to normal levels after cortical stimulation. We propose these DEGs as a potential target for motor disorder treatment in Parkinson's disease. These genes are implicated in crucial processes such as astrocyte-mediated blood vessel development and microglia-mediated phagocytosis of damaged motor neurons, suggesting their significant roles in improvement of behavior disorder. Moreover, these biomarkers not only facilitate rapid and accurate diagnosis of Parkinson's disease but also assist precision medicine approaches.

2024-07-11 | GSE271930 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data