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Computer simulations point to key molecular basis of cystic fibrosis
March 03, 2008Researchers from the University of North Carolina at Chapel Hill have identified a key molecular mechanism that may account for the development of cystic fibrosis, which about 1 in 3000 children are born with in the US every year. The findings, published February 29 in the open-access journal PLoS Computational Biology, add new knowledge to understanding the development of this disease and may also point the way to new corrective treatments.
Cystic fibrosis (CF) is a fatal disease caused by a defective gene that produces a misshapen form of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. People with cystic fibrosis do not have enough CFTR for their cells to work normally because their bodies quickly destroy the mutant protein. The deletion of this protein specifically occurs in a major domain of CFTR called NBD1. Earlier experimental studies have shown that the mutant NBD1 has an increased tendency to misfold, resulting in the premature degradation of CFTR.
In CF, the molecular basis of this increased misfolding tendency has remained elusive, said team leader Nikolay Dokholyan.
"Understanding molecular etiology of the disease is a key step to developing pharmaceutical strategies to fight this disease," Dokholyan said.
Using molecular dynamics simulations, the researchers performed extensive simulations of how normal and mutant NBD1 folded. Molecular dynamics simulation is akin to a "virtual experiment" wherein atoms and molecules are allowed to evolve according to known physical laws. Using computers, this virtual experiment allows researchers to view how atoms actually move. These simulations, when applied to the NBD1 protein, showed that the disease-causing mutant exhibits a higher misfolding tendency.
More importantly, by comparing the structures of the normal and the mutant NBD1 domains as they fold, the authors were able to determine critical pairs of amino acid residues that must come together for NBD1 to fold correctly. These interactions are modulators of CFTR folding, and hence, they are potential modulators of CF.
"Computer simulations approximate our understanding of natural phenomena. That our simulations correlated with known experimental studies is remarkable," Dokholyan said. "More importantly, the molecular details of aberrant NBD1 folding provides guidance for the design of small molecule drugs to correct the most prevalent and pathogenic mutation in CFTR."
Public Library of Science
"Understanding molecular etiology of the disease is a key step to developing pharmaceutical strategies to fight this disease," Dokholyan said.
Using molecular dynamics simulations, the researchers performed extensive simulations of how normal and mutant NBD1 folded. Molecular dynamics simulation is akin to a "virtual experiment" wherein atoms and molecules are allowed to evolve according to known physical laws. Using computers, this virtual experiment allows researchers to view how atoms actually move. These simulations, when applied to the NBD1 protein, showed that the disease-causing mutant exhibits a higher misfolding tendency.
More importantly, by comparing the structures of the normal and the mutant NBD1 domains as they fold, the authors were able to determine critical pairs of amino acid residues that must come together for NBD1 to fold correctly. These interactions are modulators of CFTR folding, and hence, they are potential modulators of CF.
"Computer simulations approximate our understanding of natural phenomena. That our simulations correlated with known experimental studies is remarkable," Dokholyan said. "More importantly, the molecular details of aberrant NBD1 folding provides guidance for the design of small molecule drugs to correct the most prevalent and pathogenic mutation in CFTR."
Public Library of Science
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Cystic Fibrosis: A Guide for Patient and Family by David M Orenstein (Editor) Univ. of Pittsburgh, PA. Text is designed specifically for patients with cystic fibrosis and their families. Explains the disease process, outlines the fundamentals of diagnosing and screening, and addresses the challenges of treatment for those living with CF. Includes new material on carrier testing, infection control, and more. Previous edition: c1997. Softcover. |
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Cystic Fibrosis: Everything You Need To Know (Your Personal Health) by Wayne Kepron MD FRCPC (Author) Cystic fibrosis afflicts approximately 30,000 Americans. The average age of survival has been steadily increasing, but not quickly enough: a child born with cystic fibrosis today can only expect to live 35 to 40 years. In this valuable new addition to the Your Personal Health series, Dr. Wayne Kepron offers a comprehensive look at the disease that afflicts so many young people. Topics include: - Symptoms of cystic fibrosis - Making a diagnosis - Complications of the disease - Treatments (including lung transplants) - Techniques and precautions in lung care - Transition into adulthood - Prospects for gene therapy - End-of-life issues Using diagrams, charts and case studies, Cystic Fibrosis is designed for patients, their families, and caregivers. It is both a quick... |
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With Every Breath: stories by and about people living with cystic fibrosis by Katherine Russell and Margot Russell (Author), Katherine Russell and Margot Russell (Editor) Over 30,000 people in the US have cystic fibrosis, a life-threatening genetic disease that affects the lungs and digestive system. Physically, fighting it is a very perilous struggle. Emotionally, coping can oftentimes be even harder. With Every Breath consists of stories by and about people living with cystic fibrosis. Created to motivate, inspire, and generate positivity for those living with cystic fibrosis, this book is something you can open time and time again. Designed for all ages, this collection of diverse stories offers unique perspectives from patients, a CF doctor and nurse, and family members of those living with the illness. Patients aren't the only ones who will want to read With Every Breath as family members, friends, and doctors can all find inspiration when they... |
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Cystic Fibrosis (Facts) by Ann Harris (Author), Anne Thomson (Author) Cystic Fibrosis: The Facts provides a much needed simple and understandable source book about this disease. It is aimed at those living with Cystic Fibrosis (CF), either themselves or members of their families or their friends. The book explains clearly what is happening to the body in CF, what causes it and what treatment options are available for the different aspects of the disease. There are more detailed chapters for those wanting to find out about the genetics of the disease and specific aspects such as how it affects life choices and employment. It looks to the future in terms of potential new therapies for CF and provides useful information on organizations that can provide help and further information across those areas of the world where the disease is prevalent. |
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The Power of Two: A Twin Triumph over Cystic Fibrosis by Isabel Stenzel Byrnes; Anabel Stenzel (Author) The tragedy of cystic fibrosis has been touchingly recounted before, but this is the first book to portray the symbiotic relationship between twins who share this life-threatening disease through adulthood. Isabel Stenzel Byrnes and Anabel Stenzel tell of their struggle to pursue normal lives while grappling with the realization that they might die young. Their story reflects the physical and emotional challenges of a particularly aggressive form of CF and tells how the twins bicultural heritage Japanese and German influenced the way they coped. The Power of Two is an honest and gripping portrayal of day-to-day health care, the impact of chronic illness on marriage and family, and the importance of a support network to continuing survival. These two remarkable sisters have much to teach... |
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The Stones Applaud: How Cystic Fibrosis Shaped My Childhood by Teresa Anne Mullin (Author) Teresa Mullin was diagnosed with cystic fibrosis at four years of age, but it was not until she was nine that she learned most children with the disease were not expected to live to adulthood. What had been a nuisance soon became a force that molded her childhood, youth, and future. In The Stones Applaud, Mullin writes of absences from school, serving as a poster child, frequent hospitalizations, medical treatments, and most painful the isolation that came with cystic fibrosis, an inherited condition that damages the lungs and affects the digestive system. With dry humor and sharp insights, Mullin describes her battles with the disease, teachers, fellow students, and even medical professionals who tried to hold her back from experiencing life. Alternately funny, frank, poignant, and... |
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Cadberry's Letters by Jennifer Racek (Author) Cadberry's mom is very forgetful. Every time they visit his doctor together she talks about C & F. She never remembers the other letters. When Cadberry draws a set of letters to help his mother remember them all, he discovers what C & F really mean and how those two tiny letters affect so much of his life. Developed for pre-school-age children, Cadberry's Letters uses simple, easy-to-follow language to explain Cystic Fibrosis and the daily care that goes along with it in terms young children can understand. Children will learn along with Cadberry about things like Pancreatic Enzymes, Chest Physical Therapy and more. Bright, full-page illustrations bring the story to life and feature a lot of the equipment and medications CF patients may use in their daily lives. |
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Cystic Fibrosis by Margaret Hodson (Author), Duncan Geddes (Author), Andrew Bush (Author) This international and authoritative work, which brings together current knowledge in the field of cystic fibrosis, has become established in previous editions as a leading reference in the field. The third edition continues to provide everything that the clinician or allied health professional treating patients with cystic fibrosis will need in a single manageable volume. Thoroughly revised and updated throughout, it reflects the significant advances that have been made in the field since the second edition published in 2000. Cystic Fibrosis outlines in detail the basic science that underlies the disease and its progression, putting it into a clinical context. Diagnostic and clinical aspects are covered in depth, as are monitoring the condition and the importance of... |
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Understanding Cystic Fibrosis (Understanding Health and Sickness Series) by Ph.D., Karen Hopkin (Author) Since the discovery of the CF gene in 1989, scientists have learned a great deal about the biology of this disease which strikes one child in every 3,300 births. With the gene pinpointed, scientists are now working on ways to replace it and are developing better tests for earlier diagnosis. Understanding CF charts the progress that has been made in a disease whose symptoms can range from mild respiratory distress to life-threatening lung infections |
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Taking Cystic Fibrosis to School by Cynthia S. Henry (Author), Cynthia S. Henry (Author), Tom Dineen (Author), Tom Dineen (Illustrator) These beautifully illustrated and fun-to-read storybooks simplify and normalize complicated childhood conditions, like cystic fibrosis. When read aloud, other children can identify why a peer may be treated differently and begin to empathize with them. In addition, children whose conditions set them apart as being different begin to feel accepted and safe. Each book includes a Kids' Quiz to reinforce new information and Ten Tips for Teachers to provide additional facts and ideas for teacher use. In Taking Cystic Fibrosis to School, Jessie explains to her classmates that even though she has cystic fibrosis, she can still attend school. |
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