Howard Jacob

..Furthermore, our data suggest that Rab38 affects urinary protein excretion via effects in the proximal tubule...

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..Previously, we have reported a novel 3-color microarray technology that enabled array fabrication QC. In this report we further investigated its advantage in spot-level data QC...

..Most importantly, this combined physiological and genomic information should also lead to the development of better pre-clinical models of human disease, which will aid in the development of new therapeutics...

..Here, we provide a high-level description and the potential uses of these new technologies for investigators using the rat for biomedical research...

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..We conclude from these studies that there are four regions within chromosome 13 containing genes that interact epistatically and influence arterial pressure...

..The development of a female rat systems biology map of cardiovascular function represents the first attempt to prioritize those regions of the genome important for development of hypertension and end organ damage in female rats...

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..These results indicate that the introgression of the CYP4A genes from Lewis rats into the Dahl S rats increases the renal formation of 20-HETE and attenuates the development of hypertension and renal disease...

..quot; These intermediate phenotypes may be used as closer surrogates to the mechanisms leading to hypertension and metabolic dysfunction in the LH rat...

..RGD houses gene, QTL and polymorphic marker data for rat, mouse and human and provides easy access to data through sophisticated searches, disease portals, interactive pathway diagrams and rat and human genome browsers...

..Because the BN chromosome is removed from its native background and the SS rat loses a native chromosome, it is also necessary to consider the contribution of changes in gene-to-gene interaction...

..This observation would suggest that clinical studies collecting participants over a wide age distribution may be diluting genetic effects and reducing power to detect true effects...

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..We have published a number of papers that provide additional information on the ontology annotations and the tools at RGD for data mining and analysis to better enable researchers to fully utilize the database...

..The impact of the rat genome project has just started, but it is an exciting time with tremendous progress...

..These data provide a baseline for physiological comparison of traits related to cardiovascular, lung, blood, and renal function in the sequenced BN rats relative to the major strains of rats studied in biomedical research...

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..The user interfaces have been adapted to the work routines of the curators, creating a suite of tools that is intuitive and powerful. Database URL: http://rgd.mcw.edu...

..Within a few years, practitioners may apply sophisticated knowledge of cell and molecular biology to expand pharmacotherapeutic approaches and to personalize diagnosis and management...

..Thus lentiviral transgenesis provides a powerful tool for the production of transgenic inbred rats and will enhance the usefulness of this species in gene discovery and target validation studies...

..This provides targets for the identification of genes involved in the regulation of hsCRP and the development and progression of vascular disease, including stroke...

..The age and severity of the presentation suggested an underlying immune defect; however, despite comprehensive clinical evaluation, we were unable to arrive at a definitive diagnosis, thereby restricting clinical management...

..The present data indicate that genes that can modify l-NAME-induced hypertension and proteinuria are on chromosomes 1, 15, 16, 18, and 20...

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..Furthermore, this consomic rat panel provides a stable genetic platform that can facilitate further gene mapping by either linkage studies or the breeding of congenic and subcongenic rats...

..By curating, storing, integrating, visualizing and promoting rat data, RGD ensures that the investment made into rat genomics and genetics can be leveraged by all interested investigators...

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..NO production and decreases uncoupled NOS3 activity. We conclude increased association of hsp90 with NOS3 is a major mechanism by which BN/Mcw hearts are more resistant to ischemia than SS/Mcw hearts...

..Qualitatively similar results were obtained from female FHH, FHH-1BN, and BN rats. The present results indicate that genes contributing to l-NAME-induced hypertension and renal disease are found on chromosome 1 of the FHH rat...

..Integrating rat physiology with mouse genetics and clinical results from human by using the respective genomes provides a novel route to capitalize on comparative genomics and the strengths of model organism biology...

..Therefore positional cloning of the gene responsible for the bleeding disorder in the FHH rat will lead to new insights in platelet physiology, with implications for diagnosis and management of hemostatic and thrombotic disorders...

..These data demonstrate a significant influence of diet composition on salt-induced hypertension and renal disease in the Dahl SS/Mcw rat...

..This new integrated RH map contains approximately 10 RH-mapped elements per Mb on the genome assembly, enabling the RH maps to serve as a scaffold for a variety of data visualization tools...

..It also demonstrates that transgenic rescue in the rat is a practical and definitive method for revealing the function of a novel gene...

..Collectively, this strategy will improve microarray data and increase its utility as a sensitive screening tool...

..This novel approach should accelerate positional cloning of mammary cancer susceptibility and resistant genes in the rat and the identification of homologous genes in humans...

..Consomic rat strains are proving to be a unique scientific resource that greatly extends our understanding of genes and complex normal and pathological function...

..These results should provide an informative source for designing future functional studies in salt-sensitive hypertension...

..Although some of these risk factors overlap with previously identified loci, none overlaps with the newly identified susceptibility locus for myocardial infarction and coronary artery disease...

..This comparative approach provides additional insight into the causes and consequences of genomic heterogeneity in recombination...

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..This technology allows for the rapid, targeted modification of the rat genome...

..In this chapter, the current state of comparative genomics and the available tools are discussed in the context of developing animal model systems that reflect the clinical picture...

..It also identifies 18 new genes that should be investigated for a role in circadian rhythms in peripheral tissues...

..Moreover, these data provide information that may be useful as new animal models, which result in novel combinations of nuclear and mitochondrial genomes, are developed...

..Automation in the fluorescent detection system and data tracking software for processing genotypes, contributes to the ability to genotype large number of samples rapidly and accurately...

..We present an overview of the database with a focus on these unique computational tools and describe strategies for the use of these resources in the area of physiological genomics...

..Our simulation results also reveal that the latent variable approach may have improved power under certain scenarios comparing with classical haplotype association methods...

..Focusing on hypertension-related phenotypes is a promising approach for identifying the genetic determinants of hypertension...

..This book focuses on a variety of methodologies that can be used in this remarkable model. This chapter sets the stage by providing a perspective on why the rat remains an important model in biomedical research...

..This chapter is designed to overview the existing sequence and its utility, as well as provide a glimpse of some of the databases and bioinformatic tools available to the investigator...

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..The aim of this study was to identify and compare gene expression differences between normal distal and proximal squamous esophageal mucosa (SM) in esophagitis patients with that of healthy controls and Barrett's patients...

..These results indicate that the T2DN rat is a suitable model for investigating diabetic nephropathy. Here we report the initial genetic and physiological characterization of this new rat model of diabetic nephropathy...

..These studies demonstrate the importance of renal infiltration of immune cells in the pathogenesis of hypertension and renal damage in Dahl SS rats...

..Thus, RGD is not only a valuable resource for those working with the rat but also for researchers in other model organisms wishing to harness the existing genetic and physiological data available in the rat to complement their own work...

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..The purpose of this study was to better define the role of these proteins by examining their expression in the rat vestibular periphery and characterizing their chromosomal location...

..By combining congenic models and cross-species studies, we narrowed the list of candidate genes to a level that we could sequence the whole interval to further identify the causative gene in future studies...

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..With the chromosomal location for each of these muscarinic subtypes known, it is now possible to develop congenic and consomic strains of rats that can be used to study the functions of each of these subtypes...

..In contrast, some features of coronary morphology, such as distal disease, do not appear to be markedly influenced by heritable factors...

..Here we present data obtained in congenic rats to directly assess the role of the Rf-1 and Rf-5 QTLs...

..These findings indicate that the Rf-1B region of the FHH rat contains at least one gene affecting the susceptibility to progressive renal failure, especially in the presence of an increase in blood pressure...

..These data suggest the close relationship between dyslipidemia in HTG rats and human FCHL, establishing a novel animal model for exploration of pathophysiology and therapy based on genomic determinants...

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..The lymphopenia mutation may thus be useful not only to elucidate Type 1 diabetes, but also in the function of the Ian gene family as a whole...

..The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease...

..In contrast, the Rf-4 QTL shows no direct effects, but significantly increases susceptibility to renal damage via an interaction with Rf-1...

..Finally, we present a set of principles that justify continuing and strengthening genetic studies in the rat model, and further development of genomic infrastructure for rat research...

..The congenic F344.lyp rat should prove useful to dissect the mechanisms by which the Ian5 frameshift mutation affects T cell selection, differentiation and maturation without organ-specific autoimmunity...

..The present study aimed to determine the presence of such interaction between the Rf-1 and Rf-5 QTLs...

..This pharmocogenetic approach enabled us to determine the main causative acute BP regulatory systems and should lead to better selection of suitable antihypertensive drugs for individual patients...

..We performed a variety of data-mining manipulations on the profiles and used complementary physiological data from the PhysGen resource to demonstrate how TREX can be used by the cardiovascular community for hypothesis generation...

..We are confident that we will either find the gene or narrow down the interval to a handful of genes when we complete the term of this grant. ..

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..A visiting scientist program will support curation, analyses and integration of specialized biological datasets. ..

..We are confident that we will either find the gene or narrow down the interval to a handful of genes when we complete the term of this grant. ..

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..Using affected/unaffected human sibpairs, we will use SNP and sequence analysis to determine if individuals exhibiting ESRD show a significant association with sequence variants in candidate genes. ..

..These proposed activities allow us to better serve the rat research community's needs and provide the wider scientific community with the ability to find, analyze and exploit rat-based data to promote their research. ..

..The combined efforts (MCW and U. of Iowa) will result in more than 1/3 of all rat genes mapped and placed on the RH "backbone" map facilitating comparative genomics with sequence "hooks". ..

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..The resulting synthesis of ideas and amassed data permits rigorous hypothesis testing not otherwise possible and will hasten understanding of the previously elusive genetic variation responsible for disease risk. ..

..The overall goal of this project is to identify genes and mechanisms involved in resistance to myocardial infarction. ..