Biobreeding rat

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Biobreeding rat also known as the BB or BBDP rat is an inbred laboratory rat strain that spontaneously develops autoimmune Type 1 Diabetes. Like the NOD mice, BB rats are used as an animal model for Type 1 diabetes. The strain re-capitulates many of the features of human type 1 diabetes, and has contributed greatly to the research of T1D pathogenesis. [1]

Rat several genera of rodents

Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus Rattus. Other rat genera include Neotoma, Bandicota and Dipodomys.

Laboratory rat inbred strains of Rattus norvegicus used for scientific research

A laboratory rat or lab rat is a rat of the species Rattus norvegicus domesticus which is bred and kept for scientific research. While less commonly used for research than mice, rats have served as an important animal model for research in psychology and biomedical science.

Non-obese diabetic or NOD mice, like the Biobreeding rat, are used as an animal model for type 1 diabetes. Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the pancreatic islets. Onset of diabetes is associated with a moderate glycosuria and a non-fasting hyperglycemia. It is recommended to monitor for development of glycosuria from 10 weeks of age; this can be carried out using urine glucose dipsticks. NOD mice will develop spontaneous diabetes when left in a sterile environment. The incidence of spontaneous diabetes in the NOD mouse is 60-80% in females and 20-30% in males. Onset of diabetes also varies between males and females: commonly, onset is delayed in males by several weeks.

Contents

Two T1D susceptibility genes have been identified in the BB rat. The susceptible MHC class II RT1u haplotype on chromosome 20 [2] and a null mutation in the GIMAP5 gene on chromosome 4. [3] The Gimap5 mutation results in severe T cell lymphopenia in the BB rat and is thought to contribute to T1D pathogenesis through impaired development and function and regulatory T cells. [4] Recently, 8 additional loci on rat chromosomes 1,2,3,6 (2 loci), 12 and 14 have been shown to be linked to Type 1 Diabetes in the BB rat. [5]

GIMAP5 protein-coding gene in the species Homo sapiens

GTPase IMAP family member 5 is an enzyme that in humans is encoded by the GIMAP5 gene.

History

BB rats are the most extensively studied rat model of T1D. They were originally derived from a Canadian colony of outbred Wistar rats that spontaneously develop hyperglycemia and ketoacidosis, characteristic of clinical onset of T1D. [6] Subsequent BB rat colonies were established. One in Worcester, Massachusetts, has been inbred and known as BBDP/Wor and another one in Ottawa, Canada, an outbred strain known as BBdp. [7]

Hyperglycemia Too much blood sugar, usually because of diabetes

Hyperglycemia, also known as high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/l (200 mg/dl), but symptoms may not start to become noticeable until even higher values such as 15–20 mmol/l (~250–300 mg/dl). A subject with a consistent range between ~5.6 and ~7 mmol/l is considered slightly hyperglycemic, while above 7 mmol/l is generally held to have diabetes. For diabetics, glucose levels that are considered to be too hyperglycemic can vary from person to person, mainly due to the person's renal threshold of glucose and overall glucose tolerance. On average however, chronic levels above 10–12 mmol/L can produce noticeable organ damage over time.

Ketoacidosis is a metabolic state associated with high concentrations of ketone bodies, formed by the breakdown of fatty acids and the deamination of amino acids. The two common ketones produced in humans are acetoacetic acid and β-hydroxybutyrate.

Worcester, Massachusetts City in Massachusetts, United States

Worcester is a city in, and the county seat of, Worcester County, Massachusetts, United States. Named after Worcester, England, as of the 2010 Census the city's population was 181,045, making it the second most populous city in New England after Boston. Worcester is located approximately 40 miles (64 km) west of Boston, 50 miles (80 km) east of Springfield and 40 miles (64 km) north of Providence. Due to its location in Central Massachusetts, Worcester is known as the "Heart of the Commonwealth", thus, a heart is the official symbol of the city. However, the heart symbol may also have its provenance in lore that the Valentine's Day card, although not invented in the city, was mass-produced and popularized by Esther Howland who resided in Worcester.

Modulation of diabetes

Diabetes in BB rats can be prevented by a single injection of mycobacterial adjuvants such as complete Freund's adjuvant (FCA). [8]

See also

Related Research Articles

Autoimmunity is the system of immune responses of an organism against its own healthy cells and tissues. Any disease that results from such an aberrant immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, sarcoidosis, systemic lupus erythematosus (SLE), Sjögren's syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis (RA), ankylosing spondylitis, polymyositis (PM), dermatomyositis (DM) and multiple sclerosis (MS). Autoimmune diseases are very often treated with steroids.

Inbred strains are individuals of a particular species which are nearly identical to each other in genotype due to long inbreeding. A strain is inbred when it has undergone at least 20 generations of brother x sister or offspring x parent mating, at which point at least 98.6% of the loci in an individual of the strain will be homozygous, and each individual can be treated effectively as clones. Some inbred strains have been bred for over 150 generations, leaving individuals in the population to be isogenic in nature. Inbred strains of animals are frequently used in laboratories for experiments where for the reproducibility of conclusions all the test animals should be as similar as possible. However, for some experiments, genetic diversity in the test population may be desired. Thus outbred strains of most laboratory animals are also available, where an outbred strain is a strain of an organism that is effectively wildtype in nature, where there is as little inbreeding as possible.

ENU chemical compound

ENU, also known as N-ethyl-N-nitrosourea (chemical formula C3H7N3O2), is a highly potent mutagen. For a given gene in mice, ENU can induce 1 new mutation in every 700 loci. It is also toxic at high doses.

Laboratory mouse animal used in labs

The laboratory mouse is a small mammal of the order Rodentia which is bred and used for scientific research. Laboratory mice are usually of the species Mus musculus. They are the most commonly used mammalian research model and are used for research in genetics, psychology, medicine and other scientific disciplines. Mice belong to the Euarchontoglires clade, which includes humans. This close relationship, the associated high homology with humans, their ease of maintenance and handling, and their high reproduction rate, make mice particularly suitable models for human-oriented research. The laboratory mouse genome has been sequenced and many mouse genes have human homologues.

Radial arm maze

The radial arm maze was designed by Olton and Samuelson in 1976 to measure spatial learning and memory in rats. The original apparatus consists of eight equidistantly spaced arms, each about 4 feet long, and all radiating from a small circular central platform. At the end of each arm there is a food site, the contents of which are not visible from the central platform.

The Rat Genome Database (RGD) is the premiere location for rat genomics, genetics, physiology and functional data, as well as data for comparative genomics between rat, human and mouse. RGD is responsible for attaching biological information to the rat genome via structured vocabulary, or ontology, annotations assigned to genes and quantitative trait loci (QTL), and for consolidating rat strain data and making it available to the research community. RGD is working with groups such as the Programs for Genomic Applications at MCW and the National BioResource Project for the Rat (NBPR-Rat) in Japan to collect and make available comprehensive physiologic data for a variety of rat strains. They are also developing a suite of tools for mining and analyzing genomic, physiologic and functional data for the rat, and comparative data for rat, mouse and human.

In genetics, two organisms that differ in only one locus and a linked segment of chromosome are defined as congenic. Similarly, organisms that are coisogenic differ in one locus only and not in the surrounding chromosome. Unlike congenic organisms, coisogenic organisms cannot be bred and only occur through spontaneous or targeted mutation at the locus.

Spontaneously hypertensive rat (SHR) is an animal model of essential hypertension, used to study cardiovascular disease. It is the most studied model of hypertension measured as number of publications. The SHR strain was obtained during the 1960s by Okamoto and colleagues, who started breeding Wistar-Kyoto rats with high blood pressure.

Zonulin is a protein that modulates the permeability of tight junctions between cells of the wall of the digestive tract. It was discovered in 2000 by Alessio Fasano and his team at the University of Maryland School of Medicine. As the mammalian analogue of zonula occludens toxin, secreted by cholera pathogen Vibrio cholerae, zonulin has been implicated in the pathogenesis of coeliac disease and diabetes mellitus type 1.

The diet-induced obesity model is an animal model used to study obesity using animals that have obesity caused by being fed high-fat or high-density diets. It is intended to mimic the most common cause of obesity in humans. Typically mice, rats, dogs, or non-human primates are used in these models. These animals can then be used to study in vivo obesity, obesity's comorbidities, and other related diseases. Users of such models must take into account the duration and type of diet as well as the environmental conditions and age of the animals, as each may promote different bodyweights, fat percentages, or behaviors.

Knockout rat

A knockout rat is a genetically engineered rat with a single gene turned off through a targeted mutation used for academic and pharmaceutical research. Knockout rats can mimic human diseases and are important tools for studying gene function and for drug discovery and development. The production of knockout rats was not economically or technically feasible until 2008.

A recombinant inbred strain is an organism with chromosomes that incorporate an essentially permanent set of recombination events between chromosomes inherited from two or more inbred strains. F1 and F2 generations are produced by intercrossing the inbred strains; pairs of the F2 progeny are then mated to establish inbred strains through long-term inbreeding.

Freund's adjuvant is a solution of antigen emulsified in mineral oil and used as an immunopotentiator (booster). The complete form, Freund's Complete Adjuvant is composed of inactivated and dried mycobacteria, whereas the incomplete form lacks the mycobacterial components. It is named after Jules T. Freund.

At least 20 different chromosomal regions have been linked to type 1 diabetes (T1D) susceptibility in humans, using genome screening, candidate gene testing, and studies of human homologues of mouse susceptibility genes.

The GAERS or Genetic Absence Epilepsy Rat from Strasbourg is a recognized animal model of absence epilepsy, a typical childhood form of epilepsy characterized by recurrent loss of contact and concomitant pattern on the electroencephalogram called "spike-and-wave" discharges. It was first characterized in Strasbourg in the 1980s and since then has been used by different international research groups to understand the mechanisms underlying absence seizures and their ontogeny, using different techniques.

Coisogenic strains are one type of inbred strain that differs by a mutation at a single locus and all of the other loci are identical. There are numerous ways to create an inbred strain and each of these strains are unique. Genetically engineered mice can be considered a coisogenic strain if the only difference between the engineered mouse and a wild-type mouse is a specific locus. Coisogenic strains can be used to investigate the gene function of a certain locus.

David Dunger is paediatric endocrinologist and chair of paediatrics at the University of Cambridge. Dunger is most notable for research into three areas, pathogenesis of type 1 diabetes and its complications, perinatal origins of risk for obesity and type 2 diabetes, and experimental medicine.

References

  1. ↑ Mordes JP, Poussier P, Blankenhorn EP, Greiner DL: Rat models of type 1 diabetes: Genetics, environment and autoimmunity. Boca Raton, CRC Press, 2007
  2. ↑ Colle, E., R.D. Guttmann, and T. Seemayer, Spontaneous diabetes mellitus syndrome in the rat. I. Association with the major histocompatibility complex. The Journal of experimental medicine, 1981. 154(4): p. 1237-42.
  3. ↑ Poussier, P., et al., Lymphopenia and abnormal lymphocyte subsets in the "BB" rat: relationship to the diabetic syndrome. Endocrinology, 1982. 110(5): p. 1825-7.
  4. ↑ Poussier, P., et al., Impaired post-thymic development of regulatory CD4+25+ T cells contributes to diabetes pathogenesis in BB rats. Journal of Immunology, 2005. 174(7): p. 4081-9.
  5. ↑ Wallis RH, Wang K, Marandi L, Hsieh E, Ning T, Chao GY, Sarmiento J, Paterson AD, Poussier P.: Type 1 diabetes in the BB rat: a polygenic disease. Diabetes. 2009 Apr;58(4):1007-17. Epub 2009 Jan 23
  6. ↑ Mordes, J.P., et al., Rat models of type 1 diabetes: genetics, environment, and autoimmunity. ILAR J, 2004. 45(3): p. 278-91.
  7. ↑ Mordes, J.P., et al., Rat models of type 1 diabetes: genetics, environment, and autoimmunity. ILAR J, 2004. 45(3): p. 278-91.
  8. ↑ Sadelain MW, Qin HY, Sumoski W, Parfrey N, Singh B, Rabinovitch A. Prevention of diabetes in the BB rat by early immunotherapy using Freund's adjuvant. J Autoimmun; 1990 ; 3:671-80. PMID   2088390
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