Howard J. Jacob, Ph.D.
Professor, Physiology and Human and Molecular Genetics
Director, Human and Molecular Genetics Center
Warren P. Knowles Chair of Genetics
Phone: (414) 456-4887
B.S. Biology, Iowa State University, 1983
Ph.D. Pharmacology, University of Iowa, 1989
|| Genetics & Genomics
|| Renal Physiology
|| Cardiovascular Physiology
||Genetic dissection of complex disease
||Disease interaction/target organ damage
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.
Huang X, Yuan T, Tschannen M, Sun Z, Jacob H, Du M, Liang M, Dittmar RL, Liu Y,
Liang M, Kohli M, Thibodeau SN, Boardman L, Wang L. Characterization of human
plasma-derived exosomal RNAs by deep sequencing. BMC Genomics. 2013;14:319. Genomics. 2013;14:319.
Liu P, Morrison C, Wang L, Xiong D, Vedell P, Cui P, Hua X, Ding F, Lu Y,
James M, Ebben JD, Xu H, Adjei AA, Head K, Andrae JW, Tschannen MR, Jacob H, Pan
J, Zhang Q, Van den Bergh F, Xiao H, Lo KC, Patel J, Richmond T, Watt MA, Albert
T, Selzer R, Anderson M, Wang J, Wang Y, Starnes S, Yang P, You M. Identification of somatic
mutations in non-small cell lung carcinomas using whole-exome sequencing. Carcinogenesis. 2012 Jul;33(7):1270-6.
Stodola TJ, de Resende MM, Sarkis AB, Didier DN, Jacob HJ, Huebner N, Hummel
O, Saar K, Moreno C, Greene AS. Characterization of the
genomic structure and function of regions influencing renin and angiogenesis in
the SS rat.Physiol Genomics. 2011 Jul
O'Meara CC, Lazar J, Hoffman M, Moreno C, Jacob HJ. Refined mapping of the renal
failure RF-3 quantitative trait locus. J Am Soc Nephrol. 2011
Adamovic T, McAllister D, Wang T, Adamovic D, Rowe JJ, Moreno C, Lazar J,
Jacob HJ, Sugg SL. Identification of novel
carcinogen-mediated mammary tumor susceptibility loci in the rat using the
chromosome substitution technique. Genes Chromosomes Cancer.
Iannaccone PM, Jacob HJ. Rats! Dis Model
Mech. 2009 May-Jun;2(5-6):206-10.
Aneas I, Rodrigues MV, Pauletti BA, Silva GJ, Carmona R, Cardoso L, Kwitek
AE, Jacob HJ, Soler JM, Krieger JE. Congenic strains provide
evidence that four mapped loci in chromosomes 2, 4, and 16 influence
hypertension in the SHR. Physiol Genomics. 2009 Mar
Dwinell MR, Worthey EA, Shimoyama M, Bakir-Gungor B, DePons J, Laulederkind
S, Lowry T, Nigram R, Petri V, Smith J, Stoddard A, Twigger SN, Jacob HJ, RGD
Team. The Rat Genome
Database 2009: variation, ontologies and pathways. Nucleic Acids
Res. 2009 Jan;37(Database issue):D744-9.
Bilusić M, Moreno C, Barreto NE, Tschannen MR, Harris EL, Porteous WK,
Thompson CM, Grigor MR, Weder A, Boerwinkle E, Hunt SC, Curb JD, Jacob HJ,
Kwitek AE. Genetically
hypertensive Brown Norway congenic rat strains suggest intermediate traits
underlying genetic hypertension. Croat Med J. 2008
Williams JM, Sarkis A, Hoagland KM, Fredrich K, Ryan RP, Moreno C, Lopez B,
Lazar J, Fenoy FJ, Sharma M, Garrett MR, Jacob HJ, Roman RJ. Transfer of the CYP4A region
of chromosome 5 from Lewis to Dahl S rats attenuates renal injury. Am
J Physiol Renal Physiol. 2008 Dec;295(6):F1764-77.
Adamovic T, McAllister D, Rowe JJ, Wang T, Jacob HJ, Sugg SL. Genetic mapping of mammary
tumor traits to rat chromosome 10 using a novel panel of consomic rats. Cancer Genet Cytogenet. 2008 Oct;186(1):41-8.
Wang T, Jacob H, Ghosh S, Wang X, Zeng ZB. A joint association test for
multiple SNPs in genetic case-control studies. Genet Epidemiol. 2009 Feb;33(2):151-63.
Dr. Jacob's CV
Link to MCW Faculty Collaboration Database - Howard Jacob