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New Research Directions

The CGS serves not only as a resource for complex instrumentation and technical know-how, but also as an incubator to: generate novel theoretical lines of inquiry into human and pathogen genetics; investigate developmental and pathological patterns of gene expression; and evaluate new paradigms for the understanding of disease process.

Towards the Development of a New Theoretical Framework for Understanding of Chronic Bacterial Pathogenesis
CGS studies into the interaction between host and pathogen in chronic bacterial infections have resulted in our positing the mucosal biofilm paradigm to explain bacterial metabolic persistence in the face of cultural sterility (Rayner, et al and Ehrlich, et al). This realization that individual bacteria can display multiple phenotypes (i.e. planktonic and biofilm) (Sauer, et al) combined with work on bacterial genomic diversity (Antalis, et al) has provided the basis for the development of a new theoretical framework termed "bacterial plurality" to understand and inform about chronic bacterial pathogenesis. The concept of genotypic plurality is embodied in the "Distributed Genome Hypothesis" and the presence of a population-based supragenome. To examine the ongoing genetic interplay between host and pathogen, we are pushing the science of comparative expressomics (identifying global changes in the patterns of gene expression) to be able to create a ''moving picture'' of gene expression throughout the various stages of biofilm development. This initiative also requires the parallel development of robust integrated bioinformatics systems which are required to provide for the cataloguing, organization, and interpretation of the vast amount of data generated via the comparative expressomic technologies.

Population-Based Comparative Genomics
Current theoretical areas of interest include the development of a battery of comparative population genomic methods (admixture, RDA, GMS, GSA subcentimorgan ancestral haplotypes) through which it will be possible to identify common differences among the various peoples of the earth. CGS staff have recently established a comparative genomics initiative with West China University of the Medical Sciences in Chengdu, Sichuan. Through numerous discussions with our Asian colleagues, it has become apparent that there are significant differences between Eastern and Western peoples in susceptibilities to: 1) infectious agents; 2) environmental toxins; and 3) various pathologic processes.

Reference List
Antalis P, Gladitz J, Shen K, Hu FZ, Sayeed S, Hayes J, Ahmed A, Johnson S, Dopico R, Chong W, Goodwin J, Singh M, Post JC, Ehrlich GD, Erdos G: Demonstration of extensive genomic plasticity among clinical isolates of nontypeable Haemophilus influenzae and evidence for a population-based supra-genome. In preparation, to be submitted to J Bacteriol.

Ehrlich GD, Veeh R, Wang X, Costerton JW, Hayes JD, Hu FZ, Daigle BJ, Ehrlich MD, Post JC: Mucosal biofilm formation on middle-ear mucosa in the chinchilla model of otitis media. JAMA 287:1710-1715, 2002.

Gorry MC, Preston RA, White GJ, Zhang Y, Singhal VK, Losken HW, Parker MG, Nwokoro NA, Post JC, Ehrlich GD: Crouzon syndrome: Mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson-Weiss syndrome. Hum Mol Gene 4:1387-1390, 1995.

Post JC, Ehrlich GD: The impact of the polymerase chain reaction in clinical medicine. JAMA 283(12):1544-1546, 2000.

Pou AM, Rimell FL, Jordan JA, Shoemaker DL, Johnson JT, Barua P, Post JC, Ehrlich GD: Adult respiratory papillomatosis: Human papillomavirus type and viral coinfections as predictors of prognosis. Ann Otol Rhinol Laryngol 104:758-762, 1995.

Rayner MG, Zhang Y, Gorry MC, Chen Y, Post JC, Ehrlich GD: Evidence of bacterial metabolic activity in culture-negative otitis media with effusion. JAMA 279:296-299, 1998.

Sauer K, Camper AK, Ehrlich GD, Costerton JW, Davies DG: Pseudomonas aeruginosa displays multiple phenotypes during development as a biofilm. J Bacteriol 184(4):1140-1154, 2002.


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