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The emergence of physiological genomics.

'Physiological genomics' represents a research paradigm shift emerging to define the functions of tens of thousands of newly discovered genes which are expected to emerge from the sequencing of the human genome and other model organisms. Genomic tools, which will allow a higher efficiency of identification of gene function, are being developed at remarkable speed. This article discusses some of the genomic and bioinformatic tools currently available or under development to provide the infrastructure for mapping and identification of gene function in simple organisms (bacteria, zebrafish, fly, worm) and complex mammalian organisms (mouse and rat). The problems facing the scientific community in the implementation of this functional approach are discussed as it is now evident that new technological and organizational infrastructures are emerging to link genes to overall function of whole organisms.

Animals↗
PubMed2002

Application of physiological genomics to the microcirculation.

Physiological genomics represents a new challenge in the biological sciences-the quest to define the functions of thousands of genes that will emerge from the sequencing of the human genome and the genomes of other model organisms. Because the attention of the scientific community has focused on this task, new tools that will allow high-efficiency identification of gene function are being developed at remarkable speed. Physiological genomic approaches to understanding integrated systems function are now becoming widely used in many areas of biological research. The availability of genomic information across species has now revealed a striking degree of conservation of both gene order and function, allowing researchers to easily move from model organisms to man in the hunt for gene function. Physiological genomics approaches in the cardiovascular system have focused on disease-based models and the behavior of large vessels. In the microcirculation, genomic studies have largely been confined to the use of single gene knockouts or to the study of angiogenesis. This review summarizes the strategies for physiological genomics that are appropriate to the study of the microcirculation and discusses several key discoveries that have been made by using these approaches.

Animals↗
PubMed2005

Tools and strategies for physiological genomics: the Rat Genome Database.

The broad goal of physiological genomics research is to link genes to their functions using appropriate experimental and computational techniques. Modern genomics experiments enable the generation of vast quantities of data, and interpretation of this data requires the integration of information derived from many diverse sources. Computational biology and bioinformatics offer the ability to manage and channel this information torrent. The Rat Genome Database (RGD; http://rgd.mcw.edu) has developed computational tools and strategies specifically supporting the goal of linking genes to their functional roles in rat and, using comparative genomics, to human and mouse. 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.

Animals↗
PubMed2002

Application of physiological genomics to the study of hearing disorders.

Although the biophysical principles of how the ear operates are reasonably well understood, little is known about the specific genes that confer normal function to the inner ear. Nevertheless, the recent implementation of genomic tools has led to extraordinary progress in the identification of mutated genes that cause non-syndromic and syndromic forms of deafness. Part of this success is directly related to the sequencing of the human and mouse genomes and improved gene annotation methods. This review discusses how physiological genomic tools, such as genomic databases, expressed sequence tag databases and DNA arrays have been applied to find candidate genes for important molecular processes in the inner ear. It also illustrates, using the discovery of genes encoding essential components of cochlear K+ homeostasis as an example, how the combination of physiological genomic tools with physiological and morphological information has led to an in-depth understanding of cochlear ion homeostasis. Finally, it discusses how the use of applied genomic tools, such as gene arrays, will further advance our knowledge of how the inner ear works, develops, ages and regenerates.

Cochlea↗
PubMed1999

Of mice and men: from early NMR studies of the heart to physiological genomics.

Just before I became an editor of Biochemical and Biophysical Research Communications in 1977 we published our first paper in this same journal on the study of tiny perfused rat hearts by (31)P NMR. In this article I trace the development of this in vivo NMR approach from the study of small rat and mouse hearts to human investigations. With the advent of molecular genetics the mouse became a key model organism for understanding and characterizing the function of human genes. I illustrate this by some of our recent work on Duchenne and Becker muscular dystrophy where the in vivo biochemical abnormalities observed in the human can be better understood from investigations of the muscle and heart of the murine model for muscular dystrophy, the mdx mouse. In particular, the mdx mouse heart exhibits ECG (conduction) abnormalities similar to that in the human which we associate with the reduction of the neuronal nitric oxide synthase activity compared to controls. We have also demonstrated in the mouse model that the increased sensitivity of the heart to ischemia is associated with a decrease in the insulin-stimulated glucose transport. Imaging techniques involving NMR, visible light, and others will play an increasingly important role in linking genomics to functional "molecular physiology."

Animals↗
PubMed2003

Physiological genomic analysis of the brain renin-angiotensin system.

The brain renin-angiotensin system (RAS) has long been considered pivotal in cardiovascular regulation and important in the pathogenesis of hypertension and heart failure. However, despite more than 30 years of study, the brain RAS continues to defy explanation. Our lack of understanding of how the brain RAS is organized at the cellular and regional levels has made it difficult to resolve long-sought questions of how ANG II is produced in the brain and the precise mechanisms by which it exerts its actions. A major reason for this is the difficulty in experimentally dissecting the brain RAS at the regional, cellular, and whole organism levels. Recently, we and others developed a series of molecular tools for selective manipulation of the murine brain RAS, in parallel with technologies for integrative analysis of cardiovascular and volume homeostasis in the conscious mouse. This review, based in part on a lecture given in conjunction with the American Physiological Society Young Investigator Award in Regulatory and Integrative Physiology (Water and Electrolyte Homeostasis Section), outlines the physiological genomics strategy that we have taken in an effort to unravel some of the complexities of this system. It also summarizes the principles, progress, and prospects for a better understanding of the brain RAS in health and disease.

Animals↗
PubMed2002

Physiological genomics: implications in hypertension research.

In this article we delineate the directions in which the study of physiology will take as it becomes integrated with genomics. We also provide specific examples of the ways in which physiological genomics may be applied to study the complex genetics of hypertension and cardiovascular disease.

Animals↗
PubMed2004

Consomic rat model systems for physiological genomics.

A consomic rat strain is one in which an entire chromosome is introgressed into the isogenic background of another inbred strain using marker-assisted selection. The development and physiological screening of two inbred consomic rat panels on two genetic backgrounds (44 strains) is well underway. Consomic strains enable one to assign traits and quantitative trait loci (QTL) to chromosomes by surveying the panel of strains with substituted chromosomes. They enable the rapid development of congenic strains over a narrow region and enable one to perform F2 linkage studies to positionally locate QTL on a single chromosome with a fixed genetic background. These rodent model systems overcome many of the problems encountered with segregating crosses where even if linkage is found, each individual in the cross is genetically unique and the combination of genes cannot be reproduced or studied in detail. For physiologists, consomics enable studies to be performed in a replicative or longitudinal manner to elucidate in greater detail the sequential expression of genes responsible for the observed phenotypes of these animals. They often provide the best available inbred control strains for physiological comparisons with the parental strains and they enable one to assess the impact of a causal gene region in a genome by allowing comparisons of the effect of replacement of a specific chromosome on a disease susceptible or a resistant genomic background. Consomic rat strains are proving to be a unique scientific resource that can greatly extend our understanding of genes and their role in the regulation of complex function and disease.

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