Mutational analyses of novel rat models with targeted modifications in inflammatory bowel disease susceptibility genes

Men, Hongsheng; Hankins, Miriam A.; Bock, Anagha S.; Beaton, Benjamin P.; Davis, Daniel R.; Chesney, Kari L.; Bryda, Elizabeth C.

doi:10.1007/s00335-021-09868-2

Cited by 3 publications

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“…Submitted 23 September 2020 / Revised 8 March 2021 / Accepted 15 March 2021 carrying the Atg16l1 T300A risk allele exhibit increased retention of bacteria within polymorphonuclear cells, greater bacterial replication and dissemination throughout the gut, and Salmonella-induced colitis (19). To further the research on the association of ATG16l1 and CD, our laboratory developed the first rat model carrying a CD risk allele, Atg16l1 T300A (F344-Atg16l1 em8Rrrc , referred to hereafter as T300A), as well as a knockout rat model of Atg16l1 (SD-Atg16l1 em2Rrrc , hereafter referred to as em2) using CRISPR-Cas 9 (43).…”

Section: Introductionmentioning

confidence: 99%

The Atg16l1 gene: characterization of wild type, knock-in, and knock-out phenotypes in rats

Chesney

Men

Hankins

et al. 2021

Physiological Genomics

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ATG16L1 is a ubiquitous autophagy gene responsible, in part, for formation of the double-membrane bound autophagosome that delivers unwanted cellular debris and intracellular pathogens to the lysosome for degradation. A single, nonsynonymous adenine to guanine polymorphism resulting in a threonine to alanine amino acid substitution (T300A) directly preceded by a caspase cleavage site (DxxD) causes an increased susceptibility to Crohn's disease (CD) in humans. The mechanism behind this increased susceptibility is still being elucidated, however, the amino acid change caused by this point mutation results in increased ATG16L1 protein sensitivity to caspase 3-mediated cleavage. In order to generate novel rat strains carrying genetic alterations in the rat Atg16l1 gene, we first characterized the wild type rat gene. We identified four alternative splice variants with tissue-specific expression. Using CRISPR-Cas9 genome editing technology, we developed a knock-in rat model for the human ATG16L1 T300A CD risk polymorphism as well as a knock-out rat model to evaluate the role of Atg16l1 in autophagy as well as its potential effect on CD susceptibility. These are the first reported rat strains with alterations of the Atg16l1 gene. Consistent with studies of the effects of human ATG16L1 polymorphisms, models exhibit morphological abnormalities in both Paneth and goblet cells, but do not develop spontaneous intestinal permeability or inflammatory bowel disease. Analysis of the gut microbiota does not show inherent differences in bacterial composition between wild type and genetically modified animals. These Atg16l1 strains are valuable new animal models for the study of both autophagy and CD susceptibility.

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Section: Introductionmentioning

confidence: 99%

The Atg16l1 gene: characterization of wild type, knock-in, and knock-out phenotypes in rats

Chesney

Men

Hankins

et al. 2021

Physiological Genomics

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Rats on the rise

Neff¹

2021

Lab Anim

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Application and perspective of CRISPR/Cas9 genome editing technology in human diseases modeling and gene therapy

Zhang,

Li,

Jin

2024

Front. Genet.

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The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) mediated Cas9 nuclease system has been extensively used for genome editing and gene modification in eukaryotic cells. CRISPR/Cas9 technology holds great potential for various applications, including the correction of genetic defects or mutations within the human genome. The application of CRISPR/Cas9 genome editing system in human disease research is anticipated to solve a multitude of intricate molecular biology challenges encountered in life science research. Here, we review the fundamental principles underlying CRISPR/Cas9 technology and its recent application in neurodegenerative diseases, cardiovascular diseases, autoimmune related diseases, and cancer, focusing on the disease modeling and gene therapy potential of CRISPR/Cas9 in these diseases. Finally, we provide an overview of the limitations and future prospects associated with employing CRISPR/Cas9 technology for diseases study and treatment.

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Mutational analyses of novel rat models with targeted modifications in inflammatory bowel disease susceptibility genes

Cited by 3 publications

References 50 publications

The Atg16l1 gene: characterization of wild type, knock-in, and knock-out phenotypes in rats

The Atg16l1 gene: characterization of wild type, knock-in, and knock-out phenotypes in rats

Rats on the rise

Application and perspective of CRISPR/Cas9 genome editing technology in human diseases modeling and gene therapy

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