The Israeli Rat Genome Center - IRGC
Yoram Yagil1, MD, FAHA Professor of Medicine; Head, Department of Nephrology and Hypertension; Head, Laboratory for Molecular Medicine and Israeli Rat Genome Center; Faculty of Health Sciences, Ben-Gurion University; Barzilai Medical Center Campus, Ashkelon. Chana Yagil 2Professor of Molecular Genetics; co-head, Laboratory for Molecular Medicine and Israeli Rat Genome Center; Faculty of Health Sciences, Ben-Gurion University Barzilai Medical Center Campus, Ashkelon
The Israeli Rat Genome Center (IRGC) was established in the early 90’s by Prof. Yoram Yagil and Prof. Chana Yagil, two scientists from the Ben-Gurion University Faculty of Health Sciences, who decided to dedicate their research activities to the study of human disease. Their focus was the investigation of complex diseases, including cardiovascular, metabolic and renal diseases. Searching for experimental animal models that would fulfill their research aspirations, they recognized the rat as a species which physiology has been studied extensively over the years and that would serve as an excellent model for the investigation of the physiology and pathophysiology of disease in humans. Seeking appropriate models, they soon became aware of a number of unique rat models of disease that had been developed in Israel by Israeli researchers and that were solely available in Israel. As these models were dispersed throughout the country, they realized that there was a need to create one central repositorium of experimental rat models of disease in Israel. This consideration and their intent to apply genomic tools to their research led them to establish the Israeli Rat Genome Center, dedicated to hosting exclusively genetically derived rat models of human disease.
The Israeli Rat Genome Center, a non-profit academic organization, was established within the compounds of the Barzilai Medical Center campus of the Ben-Gurion University Faculty of Health Sciences in Ashkelon, Israel. The Center consists of the Zootechnic Laboratory and the Laboratory for Molecular Medicine. The Zootechnic Laboratory is an animal facility that hosts genetically inbred rat strains that were developed in and that are available solely in Israel. It is staffed by a veterinarian and technicians who are highly qualified in animal care. The Laboratory for Molecular Medicine, which is operated by technical staff and post-graduate students, provides phenotyping and genomic services. It is also directing independently genomic projects seeking to unravel the genetic basis of disease, using rat models. The Israeli Rat Genome Center is funded by competitive research grants procured by its researchers, as well as by institutional research funds generously allocated by the administration of the Barzilai Medical Center.
The stated aim of the Israeli Rat Genome Center is to provide the scientific community in Israel and worldwide full access to the animal resources that are available through the Center. Its intention is to promote thereby continuing scientific research and international collaboration that will forward the understanding of normal physiology in mankind and pathophysiology of human disease, using the rat as an experimental model simulating complex diseases in humans.
The Israeli Rat Genome Center currently hosts several genetically inbred rat models of human disease. The first animal model that was donated to the Israeli Rat Genome Center was the Sabra rat model of salt-sensitive hypertension. This model was founded in the early 70’s by Professor Drori Ben-Ishay from the Hebrew University in Jerusalem, Israel. Ben-Ishay et al. (1-4) developed a genetically and phenotypically distinct line of salt-sensitive (SBH) and salt-resistant (SBN) rat strains.
The SBN and SBH substrains were available for many years solely from the original breeding colony at the animal facility of the Hebrew University Medical Center in Jerusalem. When the genetic homogeneity of that colony and its suitability for genetic studies became an issue with the appearance of reports pointing to genetic contamination of other experimental models, a nucleus from the original colony was transferred to the Israeli Rat Genome Center in 1992. Renewed selective inbreeding was initiated and an extensive effort for genetic purification of the sub-strains was undertaken and. Inbreeding has proceeded so far for over 55 generations. The products of the renewed inbreeding were designated SBH/y and SBN/y, to distinguish from the original breeding colony.
The phenotypic feature that render SBH/y and SBN/y a unique model of salt-sensitive hypertension consists of total dependence of blood pressure on dietary intake of salt. The salt-sensitive and the salt-resistant animals are normotensive at baseline, when fed regular diet with "normal" salt content. When salt-loaded, the salt-sensitive SBH/y substrain invariably develops systolic and diastolic hypertension. In contrast, the salt-resistant SBN/y substrain remains normotensive throughout its lifetime, irrespective of the amount of salt in diet. The hypertensive SBH/y substrain develops left ventricular hypertrophy and renal damage consistent with nephrosclerosis. The cardiovascular phenotypes of SBH/y or SBN/y are not affected by age, gonads or maternal environment (5).
Genome screening with microsatellite markers has demonstrated full homozygosity of the two sub-strains, qualifying them as genetically inbred (6). The presence of a large number of polymorphic markers renders these sub-strains highly suitable for genetic studies. The two sub-strains have in fact been crossbred several times, generating F1 and F2 generations, which phenotype has been determined (7;8). Congenic and consomic strains, introgressing part or entire rat chromosomes from SBH/y or SBN/y onto the genetic background of the reciprocal strain, have been constructed and are available at the Israeli Rat Genome Center (7-11). The genomes of the two sub-strains are currently being sequenced, as part of an ongoing international collaborative effort. The Genomic distribution of single nucleotide polymorphisms (SNPs) has been studied; details are available on the RGD website (http://rgd.mcw.edu/). The transcript-tome of the two sub-strains has been studied under normal diet and during salt-loading and is available for public use (12).
The SBH/y and SBN/y sub-strains are currently produced solely at the Israeli Rat Genome Center in Ashkelon, Israel. They are available for collaborative studies with laboratories interested in salt sensitivity, hypertension, target organ damage, the genetic basis of hypertension or any other related studies.
The second model that was introduced to the Israeli Rat Genome Center was the Cohen model of diabetes. This model was developed by Prof. A.M. Cohen, also from the Hebrew University. The model consists of two substrains, the Cohen Diabetic sensitive rat (CDs) and the Cohen diabetic resistant (CDr) rat.
The Cohen Diabetic rat is a genetically derived experimental model of diet-induced type 2 diabetes mellitus that reproduces many features of the disease in humans (13;14). This model stands out among other experimental rodent models of type 2 diabetes mellitus in several important ways. Its most outstanding and distinctive feature is the absolute dependence of the phenotype upon dietary pertubation, expressing genetic susceptibility (sensitivity and resistance) to a "diabetogenic diet" (15). When fed regular rat chow (normal diet), both the CDS sensitive and CDr resistant sub-strains remain normoglycemic. When fed a custom-prepared diabetogenic diet that is rich in carbohydrates and casein and poor in copper, CDs invariably develop a diabetic metabolic phenotype within one month, whereas the resistant CDr substrain maintains a normal non-diabetic phenoytpe. It is important to stress that diabetes does not develop spontaneously in these animals and is totally dependent upon diet. This unique phenotypic feature is not present in other genetically inbred rat strains that simulate type 2 diabetes in humans, including the Goto-Kakizaki (GK) (16;17), the Otsuka Long-Evens Tokushima Fatty (OLETF)(18-20) and the Zucker diabetic fatty rat (ZDF) (18;21;22) that develop diabetes spontaneously, without any important relationship to the composition of diet. Another central feature of the Cohen model is that it consists of two genetically-derived contrasting strains, originating from the same parent strain, which is useful for genetic and physiological studies. A third feature that makes the Cohen rat stand out is that it is a non-obese model of diabetes, which allows dissociation of the confounding obesity factor from other factors that induce the development of diabetes.
The original colony of the Cohen Diabetic rat model was held for many years solely at the Hebrew University animal facility of the Hadassah Medical Center in Jerusalem. In the late 90's, nearly 30 years after the colony had been originally established, a nucleus from this original breeding colony was transferred to the Israeli Rat Genome Center. A program of secondary selective re-inbreeding was undertaken in order to maximize phenotypic and genotypic homogeneity of the respective strains. Animals from the two sub-strains were selectively inbred by stringent criteria for over 10 additional generations, currently bringing overall inbreeding to >55 generations. The IRGC team subsequently studied the phenotype of the newly inbred strains and established an updated reference database for Cohen Diabetic rat model.
The metabolic phenotype the Cohen Diabetic sensitive CDs substrain that is fed regular chow consisted of fasting normoglycemia, normal glucose tolerance to glucose loading, normal fasting insulin levels and a normal insulin response to glucose loading. However, when fed a custom-prepared high-sucrose low-copper diabetogenic diet, CDs become overtly diabetic, with normal or elevated fasting glucose levels and markedly elevated plasma glucose and a reduced insulin response to glucose loading. In sharp contrast, the Cohen Diabetic Resistant CDr substrain that is fed regular or diabetogenic diet does not develop diabetes and maintains normal glucose tolerance and insulin secretion. A striking gender difference is observed in CDs that are fed diabetogenic diet: Males have a lower growth rate and a more severe glucose intolerance pattern than females (15). Gonadectomy shortly after weaning does not prevent the development of the diabetic phenotype in its early phase in either sex but markedly attenuated its expression in males at a later phase, abolishing the gender differences. Importantly, the development of the diabetic phenotype in CDs that are fed diabetogenic diet is not accompanied by obesity or hyperlipidemia.
The genetic profile of the substrains was established using 1590 microsatellite markers evenly distributed throughout the rat genome (15). The genetic homozygosity of CDs and CDr has been verified. The rate of polymorphism between the contrasting strains is 33.8%. The two substrains have been crossbred thrice, generating F1 and F2 generations which phenotype has been determined (23-25). Congenic and consomic strains, introgressing part or entire rat chromosomes from CDr onto the genetic background of CDr, have been constructed and are available at the Israeli Rat Genome Center (25).
The metabolic phenotypes of the re-bred colony of CDs and CDr and their genetic makeup render the Cohen Diabetic rat a useful experimental model that is highly suitable for studying the interaction between nutritional-metabolic environmental factors and genetic susceptibility (sensitivity and resistance) for the development of type 2 diabetes mellitus. The model is also distinctively useful for investigating the effect of gender on the expression of the diabetic phenotype. The presence of a large number of polymorphic markers renders these sub-strains highly suitable for genetic studies.
The CDs and CDr substrains are currently produced at the Israeli Rat Genome Center where they are continuously monitored for phenotypic and genetic homogeneity. They are available for collaborative studies with laboratories interested in diet induced-type 2 diabetes, the genetic basis of diabetes or any other related studies. Animals from the original colony are continuing to be produced at the Hebrew University.
The third model that was entrusted to the Israeli Rat Genome Center repository is the Cohen Rosenthal Diabetic Hypertensive (CRDH) rat. This model was developed in the early 90’s jointly by Professor Talma Rosenthal from the Tel-Aviv University Sackler Faculty of Medicine and Professor A.M. Cohen from the Hebrew University. The model combines type 2 diabetes mellitus and essential hypertension in one strain. The development of impaired glucose tolerance after feeding with diabetogenic diet involves both genetic and environmental factors. The combining of hypertension and type 2 diabetes in one experimental model provides an outstanding opportunity to study these concomitant pathologies in one animal strain (26).
The CRDH rat is a unique animal model in which genetic spontaneous hypertension and type 2 diet-induced diabetes developed after cross-breeding between the Cohen Diabetic sensitive (CDs) substrain and the Spontaneously Hypertensive Rat – (CDs x SHR) (13). In the selection process, Rosenthal and Cohen selected and mated sibling pairs with the highest spontaneous blood glucose and blood pressure. In the selected generations thereafter, diet-induced type 2 diabetes and spontaneous hypertension became evident.
The phenotype of CRDH incorporates, amongst other important features, diffuse diabetic glomerulosclerosis and hypertensive changes in arteries and arterioles that are not observed in the parental CDs or in the SHR strains. This model is thus useful in probing the mechanisms potentiating cardiovascular and renal morbid events in the setting of spontaneous hypertension and diabetes, reproducing thereby the common occurrence of type 2 diabetes and hypertension in humans (13;27;28).
The CRDH strain is currently produced at the Barzilai Medical Center in Ashkelon, as well as at the Tel-Aviv University. It is available for collaborative studies with interested laboratories, pending written consent of Prof. Talma Rosenthal.
Beyond the three major genetically derived inbred strains that were entrusted to the care of the Israeli Rat Genome Center, several additional animal models were derived within the Zootechnic facility and are currently bred within the compound. Notable among these are consomic and congenic strains originating from genetic manipulations between SBN/y and SBH/y (8-10) and between CDs and CDr (24). In these genetically derived strains, part or entire chromosomes of interest were introgressed from one strain (for example from SBN/y or CDr) onto the genetic background of contrasting strain within the same experimental model (for example SBH/y or CDs). Such strains allow investigating the contribution of introgressed chromosomal segment or entire chromosomes to phenotypes of interest. These strains are available to all interested parties on the basis of collaboration.
In addition to hosting and developing genetically derived rat models simulating diseases in humans, the investigators at the Israeli Rat Genome Center have concentrated part of their efforts on performing independent genomic research using their rat models, aiming to elucidate the genetic basis of complex diseases. Their focus has been on the investigation of the genetic basis of salt-sensitive hypertension using the Sabra rat model of salt-sensitive hypertension (6-9;29) and of type 2 diet-induced diabetes using the Cohen rat model of type 2 diet-induced diabetes (15;24;25). The renal phenotype of the Sabra model has also allowed the researchers at the Israeli Rat Genome Center to engage in the genetic dissection of proteinuria and glomerulosclerosis (10;11;30;31). The renal phenotype of the Cohen model of diabetes (32) has allowed them to initiate the genetic dissection of diabetic nephropathy (ongoing studies). In all these genetic studies, much emphasis was laid on extensive and thorough determination and documentation of the phenotype of the respective models (5;10;15;23;30;32-41), laying thereby a necessary database for future research using these animal models. The genomic research at the Israeli Rat Genome Center has incorporated positional cloning, including multiple F2 crosses between contrasting strains. These extensive and often ambitious endeavors have successfully led to the detection of novel quantitative trait loci for salt-sensitive hypertension, diet induced type 2 diabetes and proteinuria (6-9;11;24;25;31; 33;40;42;43). The genomic component of these studies has been complemented by transcriptomics, with the global study of gene expression using DNA microarrays and other means (12;25;31;33;44) that led to the identification of novel candidate genes in hypertension, diabetes and proteinuria.
One of the notable contributions of the Israeli Rat Genome Center team was the discovery of ACE2 as a candidate gene for hypertension and cardiovascular homeostasis (45;46), which would not have been possible without the work carried out by the team and its respective animal models of disease. The discovery of ACE2 has revolutionized our understanding of the renin-angiotensin system and has added a new previously unappreciated dimension to this important system that appears to be involved in multiple pathophysiological pathways incorporated within the cardiovascular, cerebrovascular, and renal systems. The interest generated in ACE2 has stimulated extensive academic research as well as a major interest of the pharmaceutical industry, which is now developing drugs based on our discoveries. The Israeli Rat Genome Center currently hosts an ACE2 transgenic animal in which the human ACE2 gene was introduced into the genome of the SBH/y rat. This model was produced by Prof. Michael Bader at the Max-Delbruck Institute for Molecular Medicine in Berlin, Germany and is currently available at our Center.
The Israeli Rat Genome Center fosters, as its binding policy, national and international collaborations. These collaborations have aimed primarily at promoting and spreading the use of the rat as an experimental animal model simulating disease in humans. The second major aim of these collaborations has been to enhance our understanding of the genetic basis of complex diseases in humans by expanding the use of our rodent models for genetic research. At the national level, the Israeli Rat Genome Center team has been actively collaborating with researchers from the Hebrew University in Jerusalem (Prof. Itamar Raz, Dr. Sarah Zangen, Prof. Michael Burzstein), the Tel-Aviv University (Prof. Talma Rosenthal, Prof. Yoni Lior, Dr. David Kaine, Dr. Adiel Barak), the Technion in Haifa (Prof. Batya Kristal, Dr. Shifra Sella), the Ben-Gurion University in Beer-Sheba (Prof. Arieh Moran, Prof. Israel Sekler, Prof. Yael Segev, Prof. Dani Landau) and the Haifa University in Haifa (Prof. Avraham Korol). At the international level, the Israeli Rat Genome Center team has been collaborating, among others, with investigators from the Max-Delbruck Center for Molecular Medicine (Prof. Detlev Ganten, Prof. Friedrich Luft, Prof. Reinhold Kreutz, Prof. Norbert Huebner, Prof. Michael Bader, Dr. Claudia Goesele, Dr. Ursula Ganten), the University of Wisconsin (Prof. Howard Jacob, Prof Martin Hessner), and Inserm in Paris, France (Prof. Liz Bankir).
In conclusion, the Israeli Rat Genome Center is a unique Israeli rat resource that holds in its possession inbred genetic rat models of common diseases that afflict a large part of humanity. The models were developed by Israeli researchers over many years of hard and intensive work and consist a valuable asset and a unique national and international resource for investigators interested in promoting our understanding of the physiology, pathophysiology and genetic basis of complex diseases, including cardiovascular, renal and metabolic diseases. The Israeli Rat Genome Center offers it resources to all interested parties on the basis of collaboration and encourages continuing as well as new collaborations nationally and worldwide.
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