Fibroblasts are relatively generic, easily maintained, human cells that form connective tissues throughout the body. By knowing the specific sequences of DNA that control the nearly 8,000 active genes in fibroblasts, scientists can tease apart the biochemical regulation system these cells use to turn genes on and off during normal growth.
The so-called "promoter map" will not only provide new insight into how genes are controlled in fibroblasts, but will also serve as a framework for analysis of genetic control in other human cell types, tissues and perhaps organs.
The project, detailed in a June 29 electronic edition of the journal, Nature, is a collaboration headed by Bing Ren at University of California, San Diego, working with scientists at University of California, Los Angeles (UCLA) and the company Nimblegen, Inc., in Madison, Wisc.
Understanding the on-off control mechanisms will further understanding of how a cell is programmed to perform specialized functions. Nearly all cells in the human body have the same genetic information. But they don't all express it at the same time. Cells in the heart, for example, express different information than do cells of the liver or brain. Controlled gene activity at certain times determines what function the cell will have in the body.
To accomplish the genome-wide promoter survey, Bing Ren and his co-worker, Tae Hoon Kim, conceived and designed a novel experimental procedure based on cutting-edge microarray technology. UCLA's Yingnian Wu and Ming Zheng developed sophisticated computer algorithms to process the massive amount of data collected from the experiments.
The researchers report that multiple promoters often control a single gene in parallel, adding another layer to an already complex genetic regulation mechanism. They also discovered promoters in front of DNA sequences not previously recognized as genes. The significance of that finding will be determined in future studies.
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Dr. Kolls' team is investigating gene-based strategies to probe the immune system's ability to fight infection in the T-cell depleted setting. In mice when T-cells are depleted, the mice are able to protect themselves against infections when given an experimental therapy that takes certain proteins secreted by T-cells “ the growth factor, IL-17, for example “ and reconstitutes them into the system. Such an approach might someday treat infections which do not respond well to antibiotics, such as pneumocystis.
The investigation of cytokines is also leading to better understanding of their role in inflammation in the lungs of patients with cystic fibrosis.
Dr. Kolls said, "I think that if we can understand the inflammation processes, we can make an impact on their lives." Dr. Kolls and his team's discovery could also have applications with Multiple Sclerosis, as well as Inflammatory Bowel Disease.
More than 30,000 patients in the United States have CF, and Pennsylvania is one of only 11 states that screen for lung disease. Dr. Kolls' lab focuses on lung immunology and host defense to address the fact that, worldwide, respiratory infections are the number one killer of children.
"Translational research is very important, especially with regards to young patients who suffer from such a chronic disease like cystic fibrosis," said Dr. Kolls. "Using research to positively impact our young patient's lives is the most rewarding part of what we do as scientists and physicians. Everything we do is really focused on how to apply that understanding and research toward bettering the outcomes and quality of life for our patients."
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