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  • Robert B. Darnell and Victor Wilson named 2010 AAAS Fellows | Newswire
    the protein lost in Fragile X mental retardation Darnell s lab also has shown that the immune systems of PND patients thwart tumors with what begins as a classical antiviral response The patients T cells produce antibodies and T cells that recognize the neuronal antigens found within their tumors They also discovered that apoptotic tumor cells serve as potent instigators of this immune response in PND patients and are developing cancer vaccines for use in small scale clinical trials performed at The Rockefeller University Hospital to mimic PND tumor immunity Darnell joined Rockefeller University in 1992 as assistant professor and associate physician at The Rockefeller University Hospital He was named associate professor in 1997 and professor and senior physician in 2000 In 2002 Dr Darnell was appointed investigator at the Howard Hughes Medical Institute and named Heilbrunn Professor at Rockefeller Darnell s awards include the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research in 2000 the Derek Denny Brown Young Neurological Scholar Award in 1998 and the Irma T Hirschl Trust Career Scientist Award in 1996 He was elected to the Institute of Medicine in 2010 Wilson a neurophysiologist was elected a AAAS Fellow for pioneering work in vestibular system physiology including characterizing the role of the vestibular labyrinth the complex of receptors in the inner ear that acts as a sixth sense by contributing to an animal s perception of its position in space and to its control of balance and posture He discovered that disinhibition occurs in the central nervous system and determined the route of nerve impulses as they flow from receptors in the vestibular labyrinth to motor neurons He is also the co author of Mammalian Vestibular Physiology one of the seminal books on the vestibular system and is a contributor to a recent volume

    Original URL path: http://newswire.rockefeller.edu/2011/01/11/robert-b-darnell-and-victor-wilson-named-2010-aaas-fellows/ (2016-02-13)
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  • RNA map gives first comprehensive understanding of alternative splicing | Newswire
    regulating alternative splicing cells can produce a wide variety of proteins from a finite number of genes This capacity is believed to be critical to the complex workings of human cells such as those found in the neurons of the brain The researchers focused on a brain protein that binds to RNA called Nova Darnell and his colleagues first identified Nova in 1993 as the target protein in a neurodegenerative disease termed POMA paraneoplastic opsoclonus myoclonus ataxia that is also associated with several types of cancers Since then the laboratory has focused on identifying RNA sequences and in particular identifying alternatively spliced pre mRNAs that Nova binds to In the last three years in work published in Science and Nature Genetics the Darnell lab identified over 50 Nova regulated alternatively spliced exons using new techniques developed at Rockefeller specifically to find Nova RNA targets and validating their results in knockout mice that were missing Nova In the new study Darnell with co first authors Jernej Ule and Giovanni Stefani took these 50 RNA transcripts and searched them for clusters of sequences they had previously identified as Nova binding sites through biochemical and in collaboration with former Rockefeller University structural biologist Stephen Burley x ray crystallographic studies Unexpectedly this search revealed four discrete peaks where the binding clusters locate Furthermore the location of the peaks correlated with Nova s action on regulating whether the alternative exon is spliced in or out The researchers tested whether this RNA map was valid by asking whether it could predict how Nova would act on RNA transcripts that had yet to be discovered They took a bioinformatics approach using a database of all alternatively spliced RNAs compiled by co authors Terry Gaasterland and Bahar Taneri to search for new genes that had clusters of Nova binding sites Of the 50 or so transcripts with such clusters 30 turned out to be alternatively spliced in a Nova dependent way Of those all 30 fit the rules of the RNA map In other words every transcript that we could predict as a Nova regulated alternatively spliced RNA fit the prediction of this map says Darnell Half of them were inhibited by Nova and half were enhanced in their exon use by Nova and every one very cleanly fit the pattern The researchers also simulated alternative splicing in the test tube mixing purified RNA and a splicing extract When purified Nova was added to the extracts it bound to the mRNA clusters altering the outcome of how the splicing machinery was able to assemble in a manner that again conformed to the predictions of the RNA map In one case Nova blocked specific components of the splicing machinery in another it enhanced the ability of this machinery to assemble the right way and use an alternatively spliced site that is otherwise poorly utilized By offering a global understanding of how alternative splicing works across the genome the map has implications for the treatment of a growing list of

    Original URL path: http://newswire.rockefeller.edu/2006/11/03/rna-map-gives-first-comprehensive-understanding-of-alternative-splicing/ (2016-02-13)
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  • RNA map | Newswire
    splicing is regulated during these processes and in some cases is uncontrolled or dysregulated to cause disease has remained elusive A new map however provides the first comprehensive understanding of how alternative splicing works throughout the genome The results have implications for a better understanding of such brain functions as learning and memory neurological diseases and cancer biology More Tags RNA map Robert B Darnell Search for Categories Science News

    Original URL path: http://newswire.rockefeller.edu/tag/rna-map/ (2016-02-13)
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  • A single protein is crucial to memory formation, scientists show | Newswire
    events that occur when brain cells signal one another Earlier we showed that Nova regulates gene expression in a way that is very special in the brain by sitting on the very top of a regulatory pyramid that begins in the cell nucleus and culminates in integrated regulation of synaptic function and plasticity says Darnell Our collaboration with Lily Jan s group validates the idea that a Nova regulated RNA network plays a role in regulation of the neuronal synapse to allow complex activities such as memory formation Jan s UCSF laboratory had been working with cells in a region of the brain called the hippocampus which is responsible for memory formation Her work recently led to the discovery of a new way in which proteins in synapses respond to memory invoking long term potentiation stimuli by potentiating or strengthening synaptic inhibition When Darnell gave a seminar at UCSF he and Jan noted that the responses her team identified relied on a number of the proteins created by the Nova regulated RNA molecules which his lab had identified in the Nature Genetics paper and in a Science paper published two years ago In the Nature Genetics study from August Darnell and his Rockefeller colleagues including Jernej Ule made RNA from the brains of normal mice and from the brains of mice that were missing Nova called knockouts They put these RNAs on a special gene chip or microarray manufactured by Affymetrix to analyze alternative splicing in a genome wide scan for Nova targets in the mouse genome To our surprise every RNA that we ve been able to validate now over 50 codes for proteins that work in the synapse of the neuron receptors proteins that cluster receptors or proteins that signal downstream from receptors in the synapse says Darnell

    Original URL path: http://newswire.rockefeller.edu/2005/10/19/a-single-protein-is-crucial-to-memory-formation-scientists-show/ (2016-02-13)
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  • Nova | Newswire
    formation scientists show New findings show that a single protein called Nova is responsible for regulating the quality of the information that is processed in the spaces between brain cells More Tags Nova Robert B Darnell Search for Categories Science News Awards and Honors Campus News Grants Gifts Topics Video Archive 2015 2014 2013 2012 2011 more About Contact Follow rockefelleruniv Like The Rockefeller University RU Footer The Rockefeller University

    Original URL path: http://newswire.rockefeller.edu/tag/nova/ (2016-02-13)
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  • Researchers describe new technique for cataloging RNA targets in rare brain disease | Newswire
    the paraneoplastic neurological disorders PNDs that the Darnell lab studies Patients suffering from the PND termed POMA are unable to inhibit movement and suffer uncontrollable shaking PNDs develop when cancer cells in the body prompt a tumor immune response that makes its way across the blood brain barrier and disrupts the normal function of brain cells The brain is known as an immune privileged site meaning that proteins expressed only in the brain are not screened by the immune system as it goes through the process of learning which proteins are self and which are foreign When a brain protein is expressed in a tumor elsewhere in the body the immune system sees it as a foreign protein and mounts a strong response against it This immune response while good for eliminating the tumor sometimes makes its way into the brain where it can attack those neurons that express the protein In the case of POMA the protein is Nova The exact nature by which the immune system attacks the brain is unclear but POMA patients have high levels of antibodies against Nova in their spinal fluid These antibodies bind a segment of Nova called the KH domain and inhibit Nova s interaction with RNA Researchers suspect that the profound dysfunction of body movement that afflicts people with POMA is caused at least in part by a direct inhibition of RNA binding by Nova antibodies In 2000 Darnell and his colleagues including Kirk B Jensen Ph D co first author of the new Science paper provided the first evidence that Nova is responsible for regulating RNA splicing in nerve cells RNA splicing is the process by which the initial RNA copy of any gene known as pre mRNA is pieced together to produce a mature mRNA that codes for cellular proteins In alternative splicing different pieces of this pre mRNA called exons are stitched together to produce different mRNAs and thus different proteins By regulating alternative splicing cells can produce a wide variety of proteins from a finite number of genes This capacity is believed to critical to the complex workings of human cells such as those found in the neurons of the brain Nova was the first RNA binding protein discovered to regulate alternative splicing specifically in the brain The finding that Nova regulates RNA splicing in neurons was satisfying as a proof of principle and raised interesting questions about Nova s function in disease says Darnell More generally for Nova and for all RNA binding proteins that are important in biology and human disease what we really want to know is what is the full array of RNAs that these proteins bind to the complete list To compile the complete list of RNAs to which Nova binds Jensen and co first author Jernej Ule combined a pair of standard techniques in the arsenal of biochemists photo cross linking and immunoprecipitation with the use of brain tissue and a number of special techniques to create a new method called

    Original URL path: http://newswire.rockefeller.edu/2003/11/14/researchers-describe-new-technique-for-cataloging-rna-targets-in-rare-brain-disease/ (2016-02-13)
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  • “Vanishing Breed” of Researchers Recognized by HHMI | Newswire
    amazing clinical phenomenon evident in PND These cDNAs have enabled us to study the disease causing mechanism of PND which has yielded a new set of insights into tumor immunity with the promise of making important discoveries about autoimmune brain disease such as multiple sclerosis directly in front of us says Darnell According to Darnell the study of the PNDs has been equally powerful as a tool for basic science discovery Here nature has pointed out for us cDNAs that are uniquely expressed in brain cells and aberrantly used by cancer cells he says This has again yielded new insights in this case into what makes a neuron different from other cells such as those found in the liver kidney or spleen For example Darnell s team found that several sets of PND proteins bind to RNA the molecules that carry genetic information from the DNA in a body cell s nucleus to its protein making machinery These studies have led a burgeoning field of research in which it is becoming apparent that such RNA binding proteins play critical roles in both brain function and brain disease Study of a PND antigen called Nova by Darnell and his colleagues Kate Dredge B Sc Giovanni Stefani M D and Kirk Jensen Ph D for example has led to new understanding of unique ways in which neurons use RNA At the same time studies by Darnell and his colleague and wife Jennifer Darnell Ph D of the related RNA binding protein FMRP have yielded insight into how errors in RNA binding lead to fragile X mental retardation In the future because the PND antigens are produced by cancer cells studying the function of these brain cancer proteins may also put us directly en route to understanding new aspects of cancer biology Darnell says The Rockefeller University Hospital is a unique modern hospital for cutting edge translational research he adds We have the opportunity to take information from a rare set of diseases to make progress in understanding more general applications this may have to humans We want to pursue our science back to where it came from human disease In studies of one form of PND called paraneoplastic cerebellar disorder PCD which is associated with breast and ovarian cancers patients suffer from severe ataxia they cannot coordinate any of the muscles in their bodies which makes it difficult to walk talk and eat Because the autoimmune brain attack is directed against only one part of the brain the cerebellum these individuals are perfectly aware and retain their cognitive abilities In studies performed at the Rockefeller Hospital Darnell working with his colleague Matthew Albert M D Ph D found that patients with PCD harbor killer T cells specific for the brain tumor PND antigen expressed in these patients gynecologic tumors and these killer T cells are the likely mediators of tumor immunity Darnell hypothesizes that killer T cells are at least partly responsible for the brain degeneration as well having found these immune

    Original URL path: http://newswire.rockefeller.edu/2002/05/28/vanishing-breed-of-researchers-recognized-by-hhmi/ (2016-02-13)
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  • Researchers Uncover Molecular Basis of Second Leading Cause of Mental Retardation | Newswire
    with the disease have abnormal physical features their dendritic spines the finger like projections on the ends of neurons that are required for communication with other neurons are unusually long and spindly The disease originates when genetic mutations in the FMRP gene which lies on the X chromosome cause FMRP not to be produced But unlike the well studied Down syndrome which occurs when a portion of a chromosome is duplicated in the womb much remains unclear about the molecular basis of fragile X syndrome The problem of fragile X is intriguing because the loss of a single protein causes a variety of behavioral and physical changes says Jennifer Darnell Ph D lead author of one of the Cell reports and a research assistant professor at Rockefeller Before this the consequences of losing the fragile X mental retardation protein on other brain proteins was unknown Previously it was known that FMRP first identified a decade ago binds to messenger RNA mRNA molecules which carry genetic information DNA from a body cell s nucleus to its protein making machinery yet the specific mRNAs involved as well as the overall purpose of this protein remained elusive Now the researchers present several important clues which together suggest that FMRP may turn up or down the production of certain brain proteins by binding to their mRNA molecules and thus influencing the cell s protein making machinery This type of protein regulation is a crucial aspect of every cell s life and in the case of brain cells is essential for learning and memory formation A key feature of the current work is the identification of the specific mRNAs that FMRP binds to as well as the finding that these molecules are misregulated in the cells of fragile X patients We found FMRP binding sites in a population of mRNAs shown to be abnormally regulated in fragile X patients says Jennifer Darnell The proteins coded for by these mRNAs are likely to underlie the problems these patients have Darnell a Rockefeller alumna first became interested in FMRP about five years ago because of its similarity to another RNA binding protein Nova under study in the laboratory of her husband Robert Darnell She identified the FMRP mRNA targets by first discovering that FMRP recognizes and tightly binds loop like structures in RNA called G quartets which represent novel human RNA binding sites This finding is intriguing because these structures which resemble in appearance loose knots along a string are typically found in DNA and not RNA the only known case of these structures existing in RNA is in bacteriophage RNA where perhaps not coincidentally they play a role in mRNA regulation A bacteriophage is a tiny virus that only infects bacteria After searching a computer database of known mRNAs for the G quartets she hit upon a significant finding several of the the mRNAs targeted by FMRP and their corresponding proteins play a role in learning and memory the development of the bones of the face

    Original URL path: http://newswire.rockefeller.edu/2001/11/16/researchers-uncover-molecular-basis-of-second-leading-cause-of-mental-retardation/ (2016-02-13)
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