 |
|
Novel method to reveal drug targets
February 25, 2008Interactions between proteins studied on a global scale
Wellcome Trust Sanger Institute scientists have developed a new large-scale method to identify the interactions between proteins that are a major target for therapeutic intervention. The novel method can identify the weak, short-lived interactions that are characteristic of cell responses to cues from the environment or from within the body.
Cell surface proteins are targets for many drugs and are central to many processes of cell regulation, such as some cancer therapeutics, diabetes, and growth. The team hope the method will uncover many important interactions that are invisible to current detection methods.
Many proteins act as molecular switches, responding to signals and activating specific genes or specific cell processes. Using biochemical tricks to increase the chances of detecting the transient and weak, but potentially important, interactions, the scientists describe 17 new pairs of interactions in mammalian cells.
"If a genome is the code for life, interactions between proteins are the communications system - the internet of our bodies," Explains Dr Gavin Wright, Junior Investigator at the Wellcome Trust Sanger Institute. "The challenge we face is that current methods cannot efficiently detect interactions at the place where communication starts: the cell surface, nor can they reliably detect transient weak interactions.
"Our new method transforms the large-scale search for these important interactions."
Unlike DNA sequencing, where methods are common to all organisms, there has been no one approach that gives a global fit for all diverse protein-protein interactions. The new method, called AVEXIS, should be applicable to interactions at the cell surface in many organisms.
Drug targets are often proteins at the surface of the cell since they are easily accessible to drugs in contrast to proteins within our cells. Unfortunately, the current catalogue of known protein interactions is biased away from these proteins simply because there was no efficient method to examine them. Effectively, a swathe of clinically important targets is invisible to research.
"AVEXIS now allows us to scale the hunt for biologically and clinically important protein-protein interactions," continues Dr Wright. "These interactions are like Velcro� - each hook can bind only weakly, but together, they can have a very strong effect. We increased the strength by gathering the proteins together, as in a small scrap of Velcro�."
The team identified previously undescribed interactions in a class of proteins called the immunoglobulin superfamily: this group of proteins shares properties that are important to allow cells to respond to their environment, talk to one another and stick together. Using human proteins and zebrafish as a model, the Sanger Institute researchers looked at interactions between 110 proteins in this superfamily - a total of more than 6000 experiments.
They found 17 interactions that met stringent standards of reliability, several of which would last for less than 0.1 seconds in cells. For each, they looked to see where the proteins were located in zebrafish embryos. They found, broadly, two categories; those in which both protein partners are present in the same tissue (and likely to be involved in cell adhesion) and those in which they are present in adjoining tissues (and therefore likely to be involved in communication between tissues). Half of the proteins interact with more than one other protein, forming interaction networks.
The results provide the first network of low-affinity interactions between proteins on the cell surface and the first set of extensive data in the zebrafish, a leading organism for following visually the effects of gene disruption.
"AVEXIS is not restricted to only one specific organism and could be used in many contexts," explains Dr Wright. "We found in the zebrafish novel interactions for well-studied proteins and can expect that we will be able to similarly enrich our understanding of human protein interactions.
"The novel interactions can lead directly to the study of protein distribution patterns and to candidates for drug targeting. If an interaction lacks one component that underlies a disease, then one can seek to find small molecules or antibodies that will act to stimulate the network at the point where the absent or dysfunctional protein would be active."
The Sanger Institute team are interested in using this method to identify the proteins on our cells to which pathogens attach: the contact between pathogen proteins and their host cell surface receptors is often the initiating event during infections. Because extracellular proteins are readily accessible to drugs delivered through the bloodstream, AVEXIS should help to identify novel therapeutic opportunities in both genetic and infectious diseases.
Wellcome Trust Sanger Institute
Many proteins act as molecular switches, responding to signals and activating specific genes or specific cell processes. Using biochemical tricks to increase the chances of detecting the transient and weak, but potentially important, interactions, the scientists describe 17 new pairs of interactions in mammalian cells.
"If a genome is the code for life, interactions between proteins are the communications system - the internet of our bodies," Explains Dr Gavin Wright, Junior Investigator at the Wellcome Trust Sanger Institute. "The challenge we face is that current methods cannot efficiently detect interactions at the place where communication starts: the cell surface, nor can they reliably detect transient weak interactions.
"Our new method transforms the large-scale search for these important interactions."
Unlike DNA sequencing, where methods are common to all organisms, there has been no one approach that gives a global fit for all diverse protein-protein interactions. The new method, called AVEXIS, should be applicable to interactions at the cell surface in many organisms.
Drug targets are often proteins at the surface of the cell since they are easily accessible to drugs in contrast to proteins within our cells. Unfortunately, the current catalogue of known protein interactions is biased away from these proteins simply because there was no efficient method to examine them. Effectively, a swathe of clinically important targets is invisible to research.
"AVEXIS now allows us to scale the hunt for biologically and clinically important protein-protein interactions," continues Dr Wright. "These interactions are like Velcro� - each hook can bind only weakly, but together, they can have a very strong effect. We increased the strength by gathering the proteins together, as in a small scrap of Velcro�."
The team identified previously undescribed interactions in a class of proteins called the immunoglobulin superfamily: this group of proteins shares properties that are important to allow cells to respond to their environment, talk to one another and stick together. Using human proteins and zebrafish as a model, the Sanger Institute researchers looked at interactions between 110 proteins in this superfamily - a total of more than 6000 experiments.
They found 17 interactions that met stringent standards of reliability, several of which would last for less than 0.1 seconds in cells. For each, they looked to see where the proteins were located in zebrafish embryos. They found, broadly, two categories; those in which both protein partners are present in the same tissue (and likely to be involved in cell adhesion) and those in which they are present in adjoining tissues (and therefore likely to be involved in communication between tissues). Half of the proteins interact with more than one other protein, forming interaction networks.
The results provide the first network of low-affinity interactions between proteins on the cell surface and the first set of extensive data in the zebrafish, a leading organism for following visually the effects of gene disruption.
"AVEXIS is not restricted to only one specific organism and could be used in many contexts," explains Dr Wright. "We found in the zebrafish novel interactions for well-studied proteins and can expect that we will be able to similarly enrich our understanding of human protein interactions.
"The novel interactions can lead directly to the study of protein distribution patterns and to candidates for drug targeting. If an interaction lacks one component that underlies a disease, then one can seek to find small molecules or antibodies that will act to stimulate the network at the point where the absent or dysfunctional protein would be active."
The Sanger Institute team are interested in using this method to identify the proteins on our cells to which pathogens attach: the contact between pathogen proteins and their host cell surface receptors is often the initiating event during infections. Because extracellular proteins are readily accessible to drugs delivered through the bloodstream, AVEXIS should help to identify novel therapeutic opportunities in both genetic and infectious diseases.
Wellcome Trust Sanger Institute
Therapeutic Intervention News and Current Therapeutic Intervention Events RSSChildhood brain tumor traced to normal stem cells gone bad
An aggressive childhood brain tumor known as medulloblastoma originates in normal brain "stem" cells that turn malignant when acted on by a known mutant, cancer-causing oncogene, say researchers from Dana-Farber Cancer Institute and the University of California, San Francisco (UCSF).
UT Pathologists Believe They Have Pinpointed Achilles Heel of HIV
Human Immunodeficiency Virus (HIV) researchers at The University of Texas Medical School at Houston believe they have uncovered the Achilles heel in the armor of the virus that continues to kill millions.
Understanding the migration of cancer cells
Lamellipodia are veil-shaped protrusions of the plasma membrane, that can turn into upward-curled ruffles if they fail to adhere to the substrate.
New data show benefit of finasteride in preventing prostate cancer
A comprehensive re-evaluation of the largest prostate cancer prevention study ever completed produced new findings suggesting that men and their doctors should consider a more aggressive approach that includes finasteride to prevent the development of prostate cancer.
Researchers report the cloning of a key group of human genes, the protein kinases
Although the human genome has been sequenced, research into mechanism of action of genes has been hampered by the fact that most human genes have not been isolated. This is true for even the most common class of cancer-associated genes, the protein kinases, which mediate the majority of signaling events in cells by phosphorylating and modulating the activity of other proteins.
Childhood leukemia survivors struggle with long-term comorbidities
Survival rates of childhood cancers, especially leukemia, have improved greatly in the past three decades, but survivors of this disease still seem to face many health and lifestyle challenges as young adults.
New guidelines update recommendations on colorectal cancer screening
A new guideline on colorectal cancer screening released today by an expert group representing a broad spectrum of health care organizations, including the American College of Gastroenterology (ACG), the American Society for Gastrointestinal Endoscopy (ASGE) and the American Cancer Society (ACS), offers recommendations for various alternatives for colorectal cancer detection and states a strong preference for screening tests that can prevent colorectal cancer.
Scripps scientists studying sepsis in mice find potential drug targets for deadly disease
"We have identified a key connection of signaling pathways in the cascade of events leading to sepsis. This defines a crucial point where the immune system spirals out of control to cause severe sepsis and where there is an opportunity for therapeutic intervention," says Scripps Research Professor Wolfram Ruf, who led the research with his postdoctoral fellow Frank Niessen.
Gene newly linked to inherited ALS may also play role in common dementia
Scientists at Washington University School of Medicine in St. Louis have linked a mutation in a gene known as TDP-43 to an inherited form of amyotrophic lateral sclerosis (ALS), the neurodegenerative condition often called Lou Gehrig's disease.
Some cases of autism may be traced to the immune system of mothers during pregnancy
New research from the UC Davis M.I.N.D. Institute and Center for Children's Environmental Health has found that antibodies in the blood of mothers of children with autism bind to fetal brain cells, potentially interrupting healthy brain development.
More Therapeutic Intervention News Articles
 | Modalities for Therapeutic Intervention (Contemporary Perspectives in Rehabilitation) With a new title and format, the 4th edition of the previously titled Thermal Agents in Rehabilitation combines all modalities in one book. Its focus remains on expanding and strengthening students' clinical decision-making skills about each modality through sample case studies. The book takes a problem-solving approach with hands-on information that describes the contemporary... |
 | Musculoskeletal Interventions: Techniques for Therapeutic Exercise by Michael L. Voight, Barbara J. Hoogenboom, William E. Prentice The definitive, A-to-Z overview of evidence-based rehab programs using therapeutic exercise In this exceptional evidence-and-guide-based, clinically-oriented resource, you'll learn everything you need to know about the design, implementation, and supervision of therapeutic exercise programs for orthopedic injuries and disorders. The book's logical five-part organization begins with an... |
 | Affect Regulation Toolbox: Practical and Effective Hypnotic Interventions for the Over-Reactive Client by Carolyn Daitch Using hypnotic techniques to facilitate successful therapy.Rational judgment, soothing behavior, and calm observation often go out the window when responding to stress. This book presents hypnotherapeutic skills (including breathing exercises) and other easy-to-learn techniques that help people maintain healthy responses to stress and facilitate effective clinical work and a happier... |
 | Animal-assisted Interventions for Individuals With Autism by Merope Pavlides |
 | Therapeutic Exercise for Physical Therapist Assistants: Techniques for Intervention (Point (Lippincott Williams & Wilkins)) Completely updated and rewritten to meet the specific needs of physical therapist assistants, this Second Edition focuses on the implementation of treatment plans and intervention using the appropriate therapeutic exercise techniques. The book describes a wide variety of therapeutic exercises and details the purpose, position, and procedure for each technique. Case studies and pediatric and... |
 | Pet Assisted Therapy: A Loving Intervention and an Emerging Profession--Leading to a Friendlier, Healthier, and More Peaceful World by Pearl Salotto Pet Assisted Therapy (PAT) features both basic information on PAT and detailed explanations of its effectiveness with children, individuals who are elderly, and those dealing with physical and mental challenges. This invaluable resource provides the reader with a thorough overview of PAT including instruction, guidelines, ethical standards, descriptions of field experiences and discussions of the... |
 | Therapeutic Exercise: Techniques for Intervention by William D Bandy, Barbara Sanders This entirely new resource focuses on the implementation of treatment plans and intervention using the newest appropriate therapeutic exercise techniques. Designed to be used after the patient has been examined and the impairment has been identified, it provides descriptions and rationale for use of a wide range of exercises to improve a patient's function and health status and to prevent... |
 | Developmental and Therapeutic Interventions in the Nicu by Elsie R. Vergara, Rosemarie Bigsby The most comprehensive book available on neonatal intervention, this in-depth resource gives professionals the strong foundation of clinical knowledge they'll need to work with high-risk newborns. With a unique developmental and therapeutic perspective that sets it apart from other texts on the subject, the book is filled with research findings and practical guidelines clinicians will... |
 | Strengthening Emotional Ties Through Parent-Child-Dyad Art Therapy: Interventions With Infants and Preschoolers by Lucille Proulx Parent-child-dyad art therapy, in which parent and child share the production of an artwork, is a new and innovative branch of art therapy. Aiming to reinforce or reestablish bonds between children and parents, it provides a space where parents' early unresolved conflicts and children's developmental abilities can be expressed. In this book, Lucille Proulx explores many aspects of dyad art... |
 | Manual for Using the Mmpi-2 As a Therapeutic Intervention by Stephen E. Finn |
| © 2008 BrightSurf.com |