Jacob, Howard Ph.D.
Professor, Physiology and Human and Molecular Genetics
Director, Human and Molecular Genetics Center
Warren Knowles Chair in Genetics
Associate Section Chief of Genetics, Childrens' Hospital of Wisconsin
Specialization: Genomics, Common Human Diseases
Tel: (414) 456-4887
Dr. Jacob's CV
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Lazar, Jozef, M.D., Ph.D.
Assistant Professor of Dermatology
Specialization: Genomics, Common Human Diseases
Tel: (414) 456-4570
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The laboratory specializes in building and implementing genomic "tools" in the whole animal. Our goal is to link genomic tools to physiology for discovering the genetic basis of disease, including end stage renal disease (rat and human), hypertension (rat), insulin dependent diabetes mellitus (rat), syndrome-X (rat), left ventricular hypertrophy, myocardial infarction (rat and human) and various cardiac malformations (human). This approach allows us to go from sequence to function using an array of systems to reduce the number of targets to a highly specific list for extensive analyses. We have the capacity to genetically map genes, positionally clone genes, and/or test candidate genes within a specific region of the genome using a new cross species homology mapping technique. With these tools we can build genetic model systems for physiological evaluation or preclinical assessment of gene based therapies.

In order to reduce the complexity of diseases such as hypertension and diabetes, inbred strains of rats have been bred and their physiology intensively studied. These rat models can then be used to dissect the genetic component of complex diseases. We maintain and study a large number of inbred strains of rat: the BB rat (insulin-dependent diabetes mellitus), BN (normotensive control, reproductive disorders), FHH rat (Fawn hooded hypertensive, ESRD model), GH rat (genetically hypertensive rat) GK rat (noninsulin-dependent diabetes mellitus, ESRD model), SHR (spontaneously hypertensive rat), SR/MCW (salt resistant), SS/MCW (salt sensitive, syndrome-X model). We have also been involved in the development of congenic rats (a single region of the genome placed on an inbred background) for hypertension (4 strains) and end stage renal disease (4 strains), and are currently developing a panel of 42 consomic (transfer of a complete chromosome from one strain to another) strains covering the entire rat genome, which will enable us to evaluate the actions of sequence variation within controlled physiological settings. We have developed a new strategy that enables us to develop new congenic strains within 6 months.

Current projects include producing consomic and subcongenic rat strains for disease studies, mapping genes involved in hypertension, renal failure, diabetes and sleep apnea. We have recently constructed a series of 28 subcongenic strains to identify the gene responsible for causing renal failure and located in the Rf-1 QTL. Microarrays and expression libraries have been obtained from different consomic strains to look for effects of chromosome substitution on response to acute ischemia. Crosses are underway to follow up an observation that some phenotypes associated with diabetic nephropathy are due to allelic differences in mitochondrial genes.