1992 — 1996 |
Kosofsky, Barry E |
K20Activity Code Description: Undocumented code - click on the grant title for more information. |
Ontogeny of Immediate Early Gene Resp to Drugs of Abuse @ Massachusetts General Hospital
This is a request for an ADAMHA SDAC which will allow me to fully focus on research, developing new skills in molecular biology. The present research proposal outlines a strategy to characterize the regional, cellular and temporal patterns of psychostimulant (cocaine and amphetamine) induced immediate early gene (IEG) expression (c-fos, c-jun, zif-268) in developing rat brain. IEG's, which function as transcription factors, may be critical effectors of drug induced neural plasticity. The proposed experiments include paradigms for acute and chronic administration of cocaine and amphetamine to rats; in utero during the last week of rat gestation, during early postnatal life and in the adult. My goal is to establish an animal model of the toxic effects of substances of abuse on developing brain, providing a mechanistic depiction of the cellular events underlying psychostimulant induced alterations of genetic programs during brain development. This grant will contribute significantly to my career development by offering me the opportunity to pursue a training initiative in molecular biology, and by providing salary support and supplies to allow me to proceed with my scientific proposal.
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0.906 |
1995 — 1999 |
Kosofsky, Barry E |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Cocaine Induced Disturbances of Mouse Brain Development @ Massachusetts General Hospital
Between 5-15% of infants born in urban America today have been exposed to cocaine in utero. There is a spectrum of outcomes for "crack kids", with prenatal and postnatal factors influencing the expression of transplacental cocaine effects. Clinical studies have suggested that the single best marker for prenatal cocaine effects, including the postnatal developmental compromise seen in a subset of affected children, is impairment of fetal and postnatal brain growth. We have developed an animal model, in mice, of prenatal cocaine exposure which has allowed us to dissociate the direct effects of cocaine in altering fetal brain development, from the indirect effects associated with cocaine-induced malnutrition. We find that transplacental cocaine exposure independently impairs fetal brain and body growth, results in transient as well as permanent behavioral disturbances in exposed offspring, and results in permanent alterations in neocortical cytoarchitecture. We have proposed experiments to investigate the determinants, correlates and mechanisms underlying these growth, behavioral, and neuropathologic changes. We will use these measures to determine whether cocaine administered during a more restricted gestational period, or at a lower dose, is sufficient to produce alterations in fetal growth and postnatal behavior, and to see whether these features can be dissociated. We propose experiments to identify and quantitate alterations in neocortical structure: a quantitative cytoarchitectonic analysis of the "barrel field" of somatosensory cortex, including measures of cortical thickness, cell density as well as characterization of anatomic markers which reflect alterations in the maturation and precision of anatomic organization of this neocortical region consequent to transplacental cocaine exposure. We propose a series of experiments to map neuronal activation to identify those brain structures and neural systems which are altered in cocaine exposed mice as adults, and which correlate with specific behavioral impairments evident in blocking of second-order aversive conditioning. Information gained from these animal studies should lead to clinical insights regarding gestational exposure to cocaine in humans, fostering improved diagnostics, treatment and prevention of one of the escalating causes of developmental disability in our society.
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0.906 |
1998 — 2002 |
Kosofsky, Barry E |
K02Activity Code Description: Undocumented code - click on the grant title for more information. |
Cocaine-Altered Brain Growth--Dopamine Knockout Analysis @ Massachusetts General Hospital
DESCRIPTION: (Applicant's Abstract) This proposal is a request for a NIDA K02 Independent Scientist Award to allow Dr. Kosofsky to further develop his research program in the field of drug abuse research. Dr. Kosofsky is a K20 award recipient, who has created an animal model (in mice) of the effects of gestational cocaine exposure on brain development. Infants born to mothers who abuse cocaine during gestation demonstrate a significant decrease in head circumference indicative of in utero compromise of brain growth and development. The animal model Dr. Kosofsky developed while being supported by the K20 has identified brain growth, neuroanatomic, behavioral, and neurochemical consequences of transplacental cocaine exposure, and has characterized some of the molecular mechanisms whereby brain is modified. This K02 research proposal outlines a strategy to further our understanding regarding the determinants, correlates and mechanisms underlying the cocaine-induced disruption of brain development. The research program outlines a strategy to utilize knockout mice that have specific deficits in dopaminergic signal transduction to characterize molecular mechanisms which may underlie some of the effects of gestational cocaine exposure in altering brain development. By utilizing knockout mice which have specific elements within the dopaminergic signal transduction pathway rendered inoperative (i.e., dopamine transporter knockouts and D1a receptor knockouts), identification of mechanisms by which dopaminergic-mediated signals are responsible for cocaine-induced alterations in brain structure will be elucidated. Neuroanatomic methods proposed include MRI microscopy, a newly developed technology capable of generating volumetric data sets that can be segmented for morphometric analysis, providing an unprecedented ability to visualize and quantitate 3-dimensional brain structure, and alterations thereof resulting from gestational cocaine exposure. One power of this approach is the combination of a unique biologic preparation (i.e., knockout mice) with an innovative technology (e.g., MRI microscopy), utilized in the service of a clinical problem of fundamental importance. In addition, this grant will contribute significantly to Dr. Kosofsky's career development by offering him the opportunity to further develop his research program on the transplacental effects of cocaine, by innovating and applying these approaches and methods.
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0.906 |
1999 — 2002 |
Kosofsky, Barry E |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Functional Brain Mapping of Cocaine Action @ Massachusetts General Hospital
While the acquisition and use of cocaine continue to have a major impact on public health and safety, advances in the understanding of how cocaine and other drugs of abuse exert their acute and chronic actions on the brain remain elusive. The development of non-invasive functional imaging techniques have provided sensitive and increasingly specific means by which neural processes can be studied with high spatial and temporal resolution. Building upon methods developed and results obtained during the first five years of finding, the experiments proposed in this competing renewal of Project 3 focus on informative rodent models, utilizing chronic cocaine self-administering rats, three lines of knockout mice, as well as drug-naive controls. We propose experiments using functional MRI (fMRI), laser doppler flowmetry, 2-DG metabolic mapping, and in vivo microdialysis methods to study mechanisms of cocaine action. Specific Aim 1 investigates the linkage between dopaminergic activity in brain reward circuits and generation of fMRI signals, and explores the role of serotonergic and GABAergic systems in modulating that activity. Specific Aim 2 utilizes fMRI in mice in which the gene coding for the dopamine transporter, or the D1a receptor, or th4e 5-HT1b receptor has been rendered inoperative. We anticipate that results from these experiments will provide confirmatory evidence to the pharmacological experiments proposed in Specific Aim 1, identifying the role of particular molecular components of dopaminergic and serotonergic signal transduction that contribute to cocaine-induced brain activation. Building upon results from Specific Aim 1, Specific Aim 3 investigates the role of dopaminergic and serotonergic systems in long-term adaptations which occur as a consequence of chronic cocaine exposure using a cocaine self- administration paradigm, the closest animal model of human substance abuse currently available. The hypothesis-driven experiments using state of the art functional imaging techniques that we have proposed in Project 1, in concert with experiments proposed in Project 2, focused on identifying mechanisms coupling psychostimulant administration to cerebral vascular response, are designed to provide a deeper understanding of the mechanism of cocaine action. These experiments in rodents will advance our understanding of acute and chronic effects of cocaine on brain function, facilitating interpretation of data from Project 1, thereby providing a crucial link in understanding the fMRI correlates and neurobiologic consequences of cocaine addiction in humans.
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0.906 |
2001 — 2003 |
Kosofsky, Barry E |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cocaine-Induced Disturbances of Mouse Brain Development @ Massachusetts General Hospital
DESCRIPTION(Provided by applicant): Gestational exposure to drugs of abuse is the single largest preventable cause of developmental compromise of infants in America today. Despite intense effort clinical progress has been slow in ascertaining the specific neurodevelopmental effects of these drugs on the children of drug-abusing mothers. Rodent models have been particularly informative regarding mechanisms underlying the acute and chronic actions of drugs of abuse. A number of animal models of developmental drug exposure suggest that cocaine may act as a behavioral teratogen, a drug capable of altering fetal brain development and subsequent function. Over the past eight years we have developed a model of transpiacental cocaine exposure in mice, and have been able to identify, and for certain outcomes separate the role of cocaine and cocaine-induced malnutrition in impairing fetal brain growth and development. Cocaine exposure in utero results in specific behavioral, anatomical and biochemical changes in mouse pups, many of which persist into adulthood. Among the reproducible changes that we observe in exposed mice that are specifically attributable to cocaine are: 1) disruptions in neuronal migration and subsequent development of cortical brain structures; 2) delayed maturation of cortical neurons utilizing the neurotransmitter GABA; 3) a persistent decrease in coupling of Dl -like receptors and their Gscoupled signals in striatum and neocortex; and 4) a persistent increase in the functional coupling of the 5-HT 1 A autoreceptor on neurons in the Dorsal Raphe. We propose a series of experiments to confirm and extend these findings characterizing specific neuroanatomical, pharmnacological, and molecular consequences induced by prenatal cocaine in particular cortical and subcortical brain structures in juvenile and adult mice. These include: Specific Aim 1) quantitative neuroanatomic studies to more accurately characterize neuropathologic changes, and in particular delayed postnatal maturation of GABAergic cells; Specific Aim 2) vitro receptor competition studies and cyclase assays to identify impaired functional coqpling of forebrain Di-like signal transduction; and Specific Aim 3) in vitro receptor competition studies and [35s]GTPyS assays to identify enhanced functional coupling of 5-HT1A autoreceptors on neurons in the Dorsal Raphe. It is hoped that our animal work may lead to identification of relevant, selective therapeutic interventions which can be utilized in clinical settings to ameliorate the toxicity, or to improve the neurodevelopmental outcome of children whose brain development is compromised following in utero cocaine exposure.
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0.906 |
2004 — 2010 |
Kosofsky, Barry E |
K02Activity Code Description: Undocumented code - click on the grant title for more information. |
Addiction Following Prenatal Cocaine Exposure @ Weill Medical College of Cornell Univ
DESCRIPTION (provided by applicant): As part of a previously NIDA funded K grant (K02DA00354) my research group has developed an animal model in Swiss Webster (SW) mice to explore mechanisms underlying long-lasting structural and functional consequences of gestational cocaine exposure. Utilizing this model we can isolate the independent effect of cocaine in contributing to altered behavioral outcomes of clinical relevance, including the liability for subsequent addiction in exposed offspring. Specifically, my laboratory has recently focused attention on studying the reinforcing efficacy of cocaine in adult animals exposed to cocaine in utero. We have pursued these studies utilizing a number of behavioral paradigms including cocaine self-administration, brain stimulation reward, and cocaine-induced locomotor sensitization. Our preliminary findings from all 3 methods suggest that mice prenatally exposed to cocaine demonstrate an augmented response to cocaine when tested as adults. As the clinical implications of these findings are profoundly important, we are proposing to further pursue our studies of cocaine-induced locomotor sensitization at a mechanistic level. The current request for a competing renewal of a NIDA Independent Scientist Award (K02) is to utilize the cocaine-induced locomotor sensitization paradigm that we have developed to identify molecular mechanisms that may underlie the augmented behavioral response to cocaine evident in adult animals exposed to cocaine in utero. We have discovered that when compared to controls, mice exposed to cocaine prenatally demonstrate a significant blunting of locomotor sensitization, and a significant augmentation of stereotypic behaviors when challenged 21 days after their last cocaine injection The goal of the research proposed in this K02 application is to confirm and extend these behavioral findings, and to identify aspects of the molecular basis of this phenomenon. By performing such experiments in a prenatal model of gestational cocaine exposure our goal will be to correlate specific patterns of molecular changes in the brain that contribute to differences in behavioral sensitization observed when comparing animals from different prenatal treatment groups. Such information will provide unique mechanistic insights regarding an enhanced vulnerability of prenatally cocaine-exposed mice to cocaine, which may lead to improved prevention of addiction in cocaine-exposed offspring.
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1 |
2004 — 2008 |
Kosofsky, Barry E |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Structural Mr Analyses of Drug Exposed Brains @ Massachusetts General Hospital
DESCRIPTION (provided by applicant): Our group proposes experiments to utilize automated segmentation tools that have been utilized on Adult MRIs to analyze a set of structural MR scans obtained from children exposed to cocaine in utero. The analysis will include both shape and contour analysis of subcortical structures, as well as the analyses of cortical structures including measurement of cortical volume, surface area, thickness, and folding pattern of the entire cortex parcellated in to specific cortical areas. By forming a collaborative imaging alliance at Brown University, our proposal will be focused on studying structural MR data from cocaine and alcohol exposed 8 to 12-year-olds. To date he and his imaging group have collected data from 14 such individuals, which we have analyzed and provide pilot data from, thereby demonstrating the feasibility and analytic power of the proposed studies. The biologic hypotheses to be tested on the drug exposed population, supported by per preliminary data, is that cocaine and alcohol induced alterations in brain development produce specific alterations in the size and shape of particular subcortical structures, and in the volume and folding pattern of particular cortical areas. Our study of shape analysis has initially focus on the corpus callosum, which in previous studies by others was shown to be altered in shape as a result of prenatal exposure to alcohol. Our morphometric studies have focused on particular cortical (orbito-frontal, frontal, and anterior cingulate) and subcortical (caudate, putamen) structures that we hypothesize are specifically altered by prenatal exposure to cocaine, with resulting functional deficits in attention, reactivity, and responsivity. We additionally propose experiments to validate our automated segmentation and morphometric methods to identify cocaine and alcohol-induced differences in the size, shape and contour brain structures of exposed children. By developing and applying such tools we will not only address a clinically important problem, but we will develop methods that will be of general value to others pursuing pediatric neuroimaging studies.
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1 |
2010 — 2014 |
Kosofsky, Barry E |
K12Activity Code Description: For support to a newly trained clinician appointed by an institution for development of independent research skills and experience in a fundamental science within the framework of an interdisciplinary research and development program. |
Wcmc Child Neurology Postdoctoral Training On Developmental Neurosciences @ Weill Medical Coll of Cornell Univ
DESCRIPTION (provided by applicant): The Weill Cornell Medical College (WCMC) Division of Child eurology proposal for a Neurological Sciences Academic Development Award (NSADA) is designed to facilitate and nurture career development for junior faculty Child Neurologists committed to independent research careers and to enable scientific training ofthe next generation of clinical neuroscientists. The Tri-lnstitutional Research Program comprising Weill Cornell Medical College, The Rockefeller University, and the Sloan-Kettering Institute ofthe Memorial Sloan-Kettering Cancer Center provides a unique environment for an NSADA Program. These three institutions recognize the national need for training biomedical investigators who: (A) have advanced understanding of biomedical neuroscience and a mastery of contemporary research skills, which will allow them to undertake fundamental studies to elucidate basic neurobiological processes pertaining to human developmental neurologic disease;and (B) are well grounded in human neurobiology, pathophysiology and clinical neurology, including child neurology. Our program will guide NSADA Scholars through a rigorous course of postgraduate study that offers flexibility regarding the individual focus of research, and unfettered access to experienced mentors in leading developmental neuroscience laboratories within the Tri-lnstitutional campus. The multi-Institutional makeup of the faculty ensures that there is broad expertise in all ofthe major research disciplines comprising developmental neuroscience in its broadest sense: neurochemistry and neurobiology;neuroanatomy and MR- based brain imaging, cell and developmental neurobiology;neuropharmacology;computational neurobiology and bioinformatics;neurogenetics and genomics;neuro-immunology;molecular neuroscience;pathology and mechanisms of disease;and neurophysiology and biophysics. While the framework of developmental neurology and medicine and the sciences ofthe infant's and child's brain in health and disease is vast, our program will emphasize the theme of having each trainee master skills in developmental neurobiology, which enable them to acquire and apply current methods in basic and clinical neurosciences to improve thir ability to diagnose and treat developmental brain disorders. PUBLIC HEALTH RELEVANCE: Our training program will allow the development of clinician researchers with the skills necessary to transfer advances in basic research to the understanding, prevention, and treatment of pediatric neurologic disorders and improve the public health.
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0.976 |
2011 — 2012 |
Kosofsky, Barry E |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Exome Re-Sequencing Candidate Loci For Familial Essential Tremor @ Weill Medical Coll of Cornell Univ
DESCRIPTION (provided by applicant): Essential tremor (ET) is one of the most common neurological disorders in humans with a prevalence reaching almost four percent. ET is inherited as a dominant trait with incomplete penetrance in most familial cases but complex multi-genic transmission is possible. Three genetic susceptibility loci for familial ET exist on chromosomes 3p13.1 (ETM1), 2p24 (ETM2), and 6p23 (ETM3), but the causal genes have not been identified in the families linked to these loci. Polymorphic ETM1 loci in 16 Icelandic families and a variant in the dopamine receptor D3 gene in 23 French families are associated with an ET phenotype. ETM2 loci are linked to a disease allele in four American families. Further studies suggest a tight allelic association between ETM2 and the ET phenotype in populations from the United States, Singapore, and Korea. Two North American families are linked to ETM3 loci with the largest family showing a mixed phenotype that includes dystonia in addition to ET. An unclear pattern of inheritance due to the presence of phenocopies, incomplete penetrance, and the high prevalence of ET, hinder the search for causal genes. Advances in solid- phase microarrays, and instrumentation have partially alleviated these barriers by permitting large scale DNA sequencing. Advances in genome bioinformatics and the availability of validated normative population databases (e.g. 1000 Genomes SNP database, dbSNP, and HapMap) provide the capability to filter genetic variants from putative mutations. By using this technology, we recently identified missense mutations in a novel gene, feline leukemia virus subgroup C receptor 1 gene, as the cause of the Mendelian disorder, posterior column ataxia and retinitis pigmentosa, in three unrelated families by high density sequencing of the 4.2 megabase (Mb) candidate region. This discovery confirms our expertise in all of the specific technologies required to carry out the proposed genetic studies and provides proof of principle for Specific Aim 1 to identify the genes that cause ET in two large, informative families linked to the ETM2 and ETM3 loci using high- throughput resequencing technology. We have designed a bait tiling library using 120 base-pair bait lengths for the 24.6 Mb ETM2 (48,054 baits) and the 14.4 Mb ETM3 (30,796 baits) loci to include all regulatory regions, exons, splice sites, enhancer, and conserved intergenic regions. A power analysis estimates that the sample size required to detect mutations with 95% confidence are 10 affected individuals with a disease haplotype and 10 unaffected individuals without the disease haplotype from each family linked to the ETM2 and ETM3 loci. Sanger sequencing will reconfirm the ETM2 and ETM3 mutations identified in the 20 affected individuals from the two families. These candidate genes will be Sanger sequenced in 73 additional, unrelated families with ET to identify other ETM2 and ETM3 mutations. Future experiments using in vitro and in vivo models will analyze the functional consequences of ET gene mutations during aging and development. PUBLIC HEALTH RELEVANCE: The identification of ET genes will improve diagnostic accuracy, refine the classification of tremor, and is a pivotal step toward finding effective treatments. Studying the untoward effects of mutant ET genes will increase our knowledge of ET and other movement disorders such as Parkinson disease.
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0.976 |
2015 — 2019 |
Kosofsky, Barry E |
K12Activity Code Description: For support to a newly trained clinician appointed by an institution for development of independent research skills and experience in a fundamental science within the framework of an interdisciplinary research and development program. |
Wcmc Child Neurology Postdoctoral Training in Developmental Neurosciences @ Weill Medical Coll of Cornell Univ
? DESCRIPTION (provided by applicant): The primary goals of the competing renewal of the Neurologic Sciences Academic Development Award (NSADA) at WCMC entitled Child Neurology Postdoctoral Training in Developmental Neuroscience (WCMC K12) are to facilitate and support career development for an additional cohort of three graduated Child Neurology residents committed to independent research careers. The previous five years of support of the WCMC K12 training program has enabled us to create a training environment and academic culture uniquely suited to train the next generation of clinical developmental neuroscientists. The current request to support the competing renewal of the WCMC K12 award is to continue to further take advantage of this uniquely stimulating environment. Renewed funding of our K12 training program will allow us to provide full salary support to allow an additional set of three graduated Child Neurology residents to each focus three years of their time and effort on developing their basic and clinical research skills. This will enable each of them to flourish as academic Child Neurologists with the ultimate goal of having them direct substantive, ongoing, independent research programs. To achieve that goal requires dedicated and protected time for graduated Child Neurology residents to train with experienced and nurturing mentors well versed in inculcating the research skills required for graduates of the WCMC K12 program to successfully compete for sustained research funding. In this proposal we outline plans for continuation and enhancement of a coherent training program, including an operational structure and organizational plan whereby that will be accomplished. In this renewal we have further expanded the set of Research Mentors who are distributed across WCMC and the Tri- institutional campus, each with active federally funded research programs, and long and distinguished track records for training clinical and basic neuroscientists. To complement the research lab driven training provided under the guidance of each NSADA Scholar's Research Mentor, each trainee participating in the WCMC K12 program will be required to obtain didactic training in clinical, translational or basic research, including the responsible conduct of researc. In addition, each NSADA Scholar will be closely guided by a team of Research and Career Mentors under the guidance of the WCMC K12 Steering Committee in the development and progression of their research project and curricular program. This will enable each NSADA Scholar's research career training to be paralleled by long-range career planning in academic Child Neurology. Within this context we propose to further develop the WCMC K12 training program that plays to the special programmatic strengths and resources in basic and clinical developmental neuroscience at WCMC and the Tri- institutional campus. Renewal of the WCMC K12 program is an institutional commitment to the self-renewal of academic Child Neurology locally and nationwide.
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0.976 |