|
 |
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.
Back
|