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MicroRNA gene that regulates lifespan found by Yale scientists
December 23, 2005
New Haven, Conn. - Genes that control the timing of organ formation during development also control timing of aging and death, and provide evidence of a biological timing mechanism for aging, Yale researchers report in the journal Science. "Although there is a large variation in lifespan from species to species, there are genetic aspects to the processes of development and aging," said Frank Slack, associate professor of Molecular, Cellular and Developmental Biology and senior author of the paper. "We used the simple, but genetically well-studied, C. elegans worm and found genes that are directly involved in determination of lifespan. Humans have genes that are nearly identical."
A microRNA and the developmental-timing gene it controls, lin-4 and lin-14, affect patterns of cellular development at very specific stages. Slack's group found that mutations in these genes alter both the timing of the worm development stages- and the worm lifespan.
C. elegans has been the premier model organism for studying the genetics of aging, and an excellent predictor of genes that also control mammalian aging.
To test their functions, they made mutants in both of these genes. Animals with a loss-of-function mutation in lin-4 had a lifespan that was significantly shorter than normal, suggesting that lin-4 prevents premature death. Conversely, over-expressing lin-4 led to a longer lifespan. They also found that a loss-of-function mutation in lin-14, the target of lin-4, caused the opposite effect - a 31 percent longer lifespan.
According to Slack, their results are strong evidence of an "intrinsic biological clock" that runs for aging as well as for normal organ development. Included results showed the developmental programs that these genes regulate are modulated through insulin signaling, demonstrating the connection between insulin-driven metabolism and aging.
"This microRNA is conserved in humans leading to the enticing idea of being able to beneficially affect the results of aging including diseases of aging," said Slack. Work is under way to identify other microRNAs regulators and genes they target, to determine where they function and whether they behave the same way in mice, and to see if they are altered in human diseases of aging.
Yale University
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MicroRNA Interference Technologies
by Zhiguo Wang (Author)
MicroRNAs (miRNAs), endogenous noncoding regulatory mRNAs of around 22-nucleotides long, have rapidly emerged as one of the key governors of the gene expression regulatory program in cells of varying species, with ever-increasing implications in the control of the fundamental biological processes and in the pathogenesis of adult humans. The exciting findings in this field have inspired us with a premise and a promise that miRNAs will ultimately be taken to the heart for therapy of human disease. While miRNAs have been considered potential therapeutic targets for disease treatment, it remains obscured what strategies we can use to achieve the goal. In the past years, we have witnessed a rapid evolving of many creative, innovative, inventive strategies and methodologies pertinent to...
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This book provides comprehensive descriptions of the innovative strategies and methodologies for detecting miRNA expression, their application in miRNA research and their potential as tools for clinical diagnosis and prognosis. It begins with the introduction of the overall concept and strategies of miRNA expression detection methods emphasizing the need of a wide variety of these methods to suit specific requirements for research and clinical examination in laboratories. In the following, each single chapter focuses on an independent, unique method of miRNA detection and is divided into five subsections: summary, introduction, protocol (including materials, instrument, reagent, and procedure), application and limitation, and reference. The development of the technique, the...
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Nearly 97 percent of the human genome is the non-coding DNA, which varies from one species to another, and changes in these sequences are frequently noticed to manifest clinical and circumstantial malfunction. Numerous non-protein-coding genes are recently found to encode microRNAs, which are responsible for RNA-mediated gene silencing through RNA interference (RNAi)-like pathways. MicroRNAs (miRNAs), small single-stranded 17-25 nucleotide RNAs capable of interfering with intracellular messenger RNAs (mRNAs) that contain either complete or partial complementarity, are useful for the design of new therapies against cancer polymorphism and viral mutation. Currently over 1000 native miRNA species found in vertebrates and many more new miRNA homologs continue to be identified; however, most...
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by Patrick J. Paddison (Author), Patrick J. Paddison (Editor), Peter K. Vogt (Editor)
In the last few years the major effect that RNAi has had in invertebrate systems like C.elegans and drosophila is beginning to take hold in mammalian systems through both single gene knockdown experiments and genome-scale screens. In the next decade, there will no doubt be both notable successes and failures as we attempt to apply this genetic tool to various biological problems for the first time in academia and industry. Through the introduction of RNAi, mammalian systems have finally gained admittance to the pantheon of model genetic systems.
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RNA interference has become a key method in the suppression of gene expression and the development of therapeutic agents, yet there is still the problem of delivery, stability, and the danger of off-target effects such as the silencing of unwanted genes and activation of innate immunity. In siRNA and miRNA Gene Silencing: From Bench to Bedside, expert researchers explore the most recent advances in siRNA design, expression, delivery, in vivo imaging, and methods to minimize siRNA’s unwanted effects and promote successful use in patients. As part of the highly successful Methods in Molecular Biology™ series, the chapters focus on their respective subjects with easy-to-use, up-to-date information, including several step-by-step laboratory protocols on topics such as new delivery...
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Regulation of Gene Expression by Small RNAs
by Rajesh K. Gaur (Editor), John J. Rossi (Editor)
New Findings Revolutionize Concepts of Gene Function
Endogenous small RNAs have been found in various organisms, including humans, mice, flies, worms, fungi, and bacteria. Furthermore, it’s been shown that microRNAs acting as cellular rheostats have the ability to modulate gene expression. In higher eukaryotes, microRNAs may regulate as much as 50 percent of gene expression.
Regulation of Gene Expression by Small RNAs brings together the pioneering work of researchers who discuss their work involving a wide variety of small RNA regulatory pathways in organisms ranging from bacteria to humans. In addition to exploring the biogenesis and processing of these regulatory RNAs, they also consider the functional importance of these pathways in host organisms. Assisting...
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Gene Profiles in Drug Design
by Brett A. Lidbury (Editor), Suresh Mahalingam (Editor)
With the successful mapping of the human genome, we have entered an age of unprecedented opportunity in which researchers are beginning to apply this vast repository of knowledge to the treatment of human disease. Gene-profiling technologies and the concept of individualized medicine are leading to the development of drugs with enhanced specificity. This promises to lead to more effective treatment of diseases with reduced risk of side effects. Gene Profiling in Drug Design provides insights from leaders in the pure sciences, biotechnology, and other arenas. It emphasizes the science that underpins gene profiling and drug development, and also includes clinical and ethical perspectives from experts in those fields. These explore the broadest health and social implications for this...
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Bioinformatics Research and Development: Second International Conference, BIRD 2008, Vienna, Austria, July 7-9, 2008 Proceedings (Communications in Computer and Information Science)
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This book constitutes the refereed proceedings of the Second International Bioinformatics Research and Development Conference, BIRD 2008, held in Vienna, Austria in July 2008. The 49 revised full papers presented were carefully reviewed and selected. 30 papers are organized in topical sections followed by 11 papers from the ALBIO workshop and 8 papers from the PETRIN workshop.
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Small RNAs:: Analysis and Regulatory Functions (Nucleic Acids and Molecular Biology)
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In recent years Molecular Biology has experienced an unprecedented revolution by the discovery of functional small RNAs. The number of cellular processes in which non-coding RNAs are involved is growing rapidly and include gene regulation on the transcriptional, post-transcriptional and translational level. To complicate matters, these processes seem to be strongly interconnected on the one hand, and diverse among different organisms on the other. This volume describes strategies for the discovery and validation of small RNAs and provides a snapshot of our current understanding of the different mechanisms triggered by small RNAs.
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