1998 — 2001 |
Pevsner, Jonathan |
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. |
Mechanisms of Vesicle Trafficking to Lysosomes in Brain @ Hugo W. Moser Res Inst Kennedy Krieger
DESCRIPTION: The long term objective of the proposed research is to determine how vesicles are targeted to lysosomes in normal brain and in several neurological diseases. Lysosomes are acidic organelles that are enriched in hydrolases, and capable of degrading both internalized and endogenous macromolecules. Their functional importance is highlighted by the occurrence of several dozen lysosomal disorders which cause neurological damage. Throughout the cell, highly specific vesicles trafficking is essential to allow cargo to be sent to the appropriate destination. This vesicle trafficking occurs in a specific fashion by the formation of protein-protein complexes between vesicle proteins, cytosolic proteins, and target membrane proteins. The investigators have identified brain cDNA clones encoding four proteins that may responsible for vesicle trafficking to lysosomes. These are syntaxin (homologous to yeast Pep 12p) and three proteins related to n-sec1 (mammalian homologues of yeast Vps33p and Vps45p). The specific aims are as follows: (1) determine the subcellular localization of these presumed lysosomal proteins in brain, in normal human fibroblasts, and in fibroblasts, and in fibroblasts derived from patients with neurological disorders affecting lysosome function (such as Chediak-Higashi syndrome, Niemann-Pick disease type C, and muculipidosis IV). (2) Identify syntaxin-containing protein complexes implicated in vesicle trafficking to brain lysosomes, analogous to those complexes characterized in the presynaptic nerve terminal. These studies may contribute to our understanding of the proteins that mediate vesicle trafficking to lysosomes in neurons and other cell types. Such information may be important to understand the molecular defects in a variety of neurological disorders in which intracellular transport to (or from) lysosomes is defective.
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0.915 |
1998 — 2002 |
Pevsner, Jonathan |
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. |
Molecular Mechanisms of Lead Neurotoxicity @ Hugo W. Moser Res Inst Kennedy Krieger
DESCRIPTION: The long-term goal of this project is to understand fundamental molecular mechanisms by which lead mediates increased neurotransmitter release. Several lines of evidence support the thesis that lead interferes with the coordinated regulation of synaptic loading, vesicular movement, docking and fusion with presynaptic membranes. Recent biochemical data, employing in the vivo and in the vitro models, provides compelling evidence implicating lead-mediated perturbation of normal vesicular trafficking processes resulting in the inappropriate release of neurotransmitters in the neuromuscular in the inappropriate release of neurotransmitters in the neuromuscular junction, synaptosomes and in the permeabilized cell cultures. Preliminary data obtained in the response to previous review further strengthens the principal investigator's assertion that the effects of lead on ephaptic synaptic release of neurotransmitters may be mediated by binding to the regulatory protein synaptotagmin. However, the exact mechanism(s) of lead-induced spontaneous neurotransmitter release remain to be determined. The hypothesis that lead binds to synaptotagmin and, therefore, stimulates unscheduled release of neurotransmitters is addressed by three specific aims. Proposed experiments are aimed at understanding (1) the pharmacology of lead- binding to the calcium-dependent regulatory protein, synaptotagmin; (2) the role of lead-synaptotagmin complexes in the unscheduled neurotransmitter release; and (3) the alteration of lead-effects on proposed in the this revised submission may provide new insights into the role of lead in the perturbation of normal synaptic vesicular function.
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0.915 |
2003 — 2007 |
Pevsner, Jonathan |
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. |
Effects of Lead On Calcium-Binding Proteins in Rats @ Hugo W. Moser Res Inst Kennedy Krieger
[unreadable] DESCRIPTION (provided by applicant): The major long-term objectives of the proposed research are [1] to test the hypothesis that lead interacts with calcium binding proteins of the C2 and annexin families, and [2] to identify genes and proteins of these calcium-binding families that are regulated following lead exposure of rats. Lead poisoning remains a pervasive problem in the United States, affecting at least 5% of all children. The proposed research is intended to elucidate molecular mechanisms underlying lead toxicity. Previous studies have demonstrated potent interactions between lead and proteins of the C2 domain family (e.g. protein kinase C and synaptotagmin) and annexins. Furthermore, lead exposure of cells has been shown to regulate the expression of genes encoding calcium-binding annexins. The four specific aims of this proposal are [1] to measure the interactions of lead with proteins of the C2 domain and annexin families, in order to determine the possible targets of lead. [2] To measure gene expression in the brain, kidney and liver of lead-exposed rats. This in vivo model may reveal whether lead exposure differentially regulates the expression of genes encoding calcium-binding proteins. [3] To extend gene expression studies to well characterized cell lines (astrocytes, PC12 cells, fibroblasts and normal rat kidney cells). These studies will complement gene expression measurements from the in vivo model. [4] To deposit gene expression data into a publicly accessible database. Together these studies may reveal which calcium binding proteins interact with lead, and which genes encoding calcium-binding proteins are regulated by lead exposure. [unreadable] [unreadable]
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0.915 |
2004 — 2006 |
Pevsner, Jonathan |
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. |
Regulation of Gene Expression in Down Syndrome @ Hugo W. Moser Res Inst Kennedy Krieger
DESCRIPTION (provided by applicant): The broad, long-term objective of the proposed research is to define the consequence of trisomy 21 (Down syndrome) on transcription (gene expression) and translation. Down syndrome is the most frequently occurring cause of mental retardation known to be associated with a chromosomal abnormality. It is caused by a complete or partial trisomy (triplicate state) of chromosome 21. Individuals with Down syndrome have mental retardation to varying degrees, as well as dozens of other phenotypic abnormalities. It is not known how the trisomy of chromosome 21 causes neurological or other pathological phenotypes. The specific aims are as follows: [1] Perform gene expression profiling with trisomy 21 postmortem cerebrum, cerebellum, and heart samples relative to euploid controls. The purpose of these studies is to test the hypothesis that there is a global up-regulation of gene expression in genes assigned to chromosome 21. Through gene expression profiling and subsequent confirmation studies, we will define specific genes that are differentially regulated in trisomy 21 tissues. [2] Determine the transcriptional profile in lymphoblast cell lines from Down syndrome patients and euploid controls. These patients have been clinically characterized (e.g. with neurobehavioral evaluations and brain imaging) and are classified as having severe or mild forms of Down syndrome. We will test the hypothesis that the severity of the clinical phenotype correlates to the magnitude of gene expression changes. [3] While the first two aims address transcriptional changes, in this aim we test the hypothesis that translation is regulated in Down syndrome. We will perform quantitative immunoblotting of fetal brain and heart as well as lymphoblasts. [4] The mechanisms we study in Down syndrome may be relevant to other aneuploidies. We will determine the transcriptional profile in frozen brain and lymphoblasts from individuals with trisomy 13 (Patau syndrome) and trisomy 18 (Edwards syndrome). These are the other major trisomies compatible with life. We will test the hypothesis that in cells derived from these individuals there is a global up-regulation of the expression of genes assigned to chromosomes 13 and 18, respectively.
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0.915 |
2005 — 2008 |
Pevsner, Jonathan |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Core 4: Training @ Johns Hopkins University
1, 5-dihydro-5-methyl-1-(5-O-phosphono-.beta.-D-ribofuranosyl)-1,4,5, 6,8-pentaazaacenaphthylen-3-amine; 1,4, 5,6,8-pentaazaacenaphthylen-3-amine, 1, 5-dihydro-5-methyl-1-(5-O-phosphono-.beta.-D-ribofuranosyl)- (9CI); 1,4,5,6, 8-pentaazaacenaphthalen-3-amine, 1, 5-dihydro-5-methyl-1-(5-O-phosphono-.beta.-D-ribofuranosyl); 1,4,5,6,8-pentaazaacenaphthylene-3-amino-1,5-dihydro-5-methyl-1-beta-D-ribofuranosyl 5'-phosphate ester; 3-amino-1, 5-dihydro-5-methyl-1-.beta.-D-ribofuranosyl-1,4,5,6, 8-pentaazaacenaphthylene 5'-(dihydrogen phosphate); Appointment; Bio-Informatics; Biochemistry; Bioinformatics; CRISP; Chemistry, Biological; Complement; Complement Proteins; Computational Biology; Computer Retrieval of Information on Scientific Projects Database; Funding; Grant; Institutes; Institution; Investigators; NIH; National Institutes of Health; National Institutes of Health (U.S.); Pathway interactions; Proteins; Proteomics; Research; Research Personnel; Research Resources; Researchers; Resources; Schools, Medical; Source; TCN-P; TCNP; Time; Training; Triciribine Phosphate; Tricyclic Nucleoside 5'-Phosphate; Tricycloside Phosphate; United States National Institutes of Health; Universities; gene product; medical schools; pathway
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0.955 |
2015 — 2019 |
Pevsner, Jonathan |
U01Activity 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. |
Role of Somatic Mosaicism in Autism, Schizophrenia, and Bipolar Disorder Brain @ Hugo W. Moser Res Inst Kennedy Krieger
? DESCRIPTION (provided by applicant): The broad, long-term objective of the proposed research is to identify somatic genetic mutations that occur in brain regions of individuals with autism spectrum disorder (ASD), schizophrenia (SZ), and bipolar disorder (BD). Ultimately the discovery and characterization of somatic mutations may help us to understand the etiology of these disorders and eventually lead to improved therapeutic strategies and diagnostic markers. ASD, SZ, and BD are all commonly occurring neuropsychiatric disorders that have a large genetic basis (with estimated heritability of ~75% to 80% for each condition). However, relatively few DNA variants have been identified that have causal roles in the etiology. We hypothesize that somatic mosaicism--the occurrence of mutations in selected body regions after conception--occurs in brain and contributes to the etiology of ASD, SZ, and BD. Specific Aim 1 is to identify the nature and extent of somatic mosaic mutations across brain and body regions in postmortem samples from apparently normal individuals. We will assess four categories of somatic variation: (1) single nucleotide variants (SNVs), (2) structural variants (SVs) including copy number variants, (3) L1 retrotransposition events, and (4) mitochondrial heteroplasmy. These types of variation will be detected using whole genome sequencing (Years 1 and 2), single molecule imaging with DNA nanochannels (Year 2), and single nucleotide polymorphism (SNP) arrays. Samples include brain regions (e.g. prefrontal cortex and cerebellum) and organs (e.g. heart and kidney). After identifying somatic variants we will perform rigorous validation. Specific Aim 2 is to identify the nature and extent of somatic mosaicism in genomic DNA from individuals with ASD, SZ, and BD. The same approaches for discovery and validation will be applied as in Aim 1. Specific Aim 3 is to functionally categorize somatic variants, particularly those that are predicted to disrupt the functions of genes previously implicated in those disorders. One approach is single-cell RNA-seq (to determine the consequence of the mutation on transcription, and to infer the cell type of origin of the somatic variant). Another approach uses neurons (or glia) derived from induced pluripotent stem cells (iPSCs) and stably expressing the wildtype or mutant forms of the somatic variants. These studies will help to establish the role of somatic mutation in neuropsychiatric disorders, including the functional consequences of such variation.
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0.915 |
2020 |
Pevsner, Jonathan |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Intellectual and Developmental Disabilities Research Centers 2020 @ Hugo W. Moser Res Inst Kennedy Krieger
PROJECT SUMMARY/ABSTRACT ? GENOMICS CORE The goal of the Genomics Core is to provide IDDRC-supported projects with access to state-of-the-art technology and expertise relevant to understanding genetic factors associated with intellectual and developmental disabilities (IDD). The Genomics Core accomplishes its mission through four specific aims. In Aim 1, the Core provides consultation services for genomics research. These services include facilitating protocol development for IRB-approved human subject research, offering guidance to researchers and clinicians about study design and appropriate utilization of next-generation sequencing technologies and specialized genomics applications, and offering assistance in grant applications that involve genomics projects. The second Aim is to provide genomics services in the general areas of next-generation sequencing, genotyping, cytogenetics and chromosomal microarray analysis. This includes specialized genomic services ranging from whole exome and whole genome sequencing, RNA-seq, and ChIP-seq to single molecule sequencing. The Core offers a full-service CAP certified biorepository. For Aim 3 the Genomics Core assists with data analysis, offering guidance on the use of compute resources to store and analyze data including the interpretation of genomics data. Aim 4 is to provide educational activities and dissemination opportunities, including a variety of workshops and classes. These Specific Aims are integrated with each other and with other Cores of the IDDRC. The Genomics Core places a heavy emphasis on the etiology, natural history and prognosis of a variety of conditions associated with developmental delay and specific features of developmental disabilities. This emphasis helps IDDRC researchers to elucidate the phenotypic variations which are associated with genetic mutations (e.g., chromosomal anomalies, genomic copy number changes, single nucleotide variation and short insertions and deletions [indels]).
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0.913 |
2021 |
Pevsner, Jonathan |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Genomics Core @ Hugo W. Moser Res Inst Kennedy Krieger
PROJECT SUMMARY/ABSTRACT ? GENOMICS CORE The goal of the Genomics Core is to provide IDDRC-supported projects with access to state-of-the-art technology and expertise relevant to understanding genetic factors associated with intellectual and developmental disabilities (IDD). The Genomics Core accomplishes its mission through four specific aims. In Aim 1, the Core provides consultation services for genomics research. These services include facilitating protocol development for IRB-approved human subject research, offering guidance to researchers and clinicians about study design and appropriate utilization of next-generation sequencing technologies and specialized genomics applications, and offering assistance in grant applications that involve genomics projects. The second Aim is to provide genomics services in the general areas of next-generation sequencing, genotyping, cytogenetics and chromosomal microarray analysis. This includes specialized genomic services ranging from whole exome and whole genome sequencing, RNA-seq, and ChIP-seq to single molecule sequencing. The Core offers a full-service CAP certified biorepository. For Aim 3 the Genomics Core assists with data analysis, offering guidance on the use of compute resources to store and analyze data including the interpretation of genomics data. Aim 4 is to provide educational activities and dissemination opportunities, including a variety of workshops and classes. These Specific Aims are integrated with each other and with other Cores of the IDDRC. The Genomics Core places a heavy emphasis on the etiology, natural history and prognosis of a variety of conditions associated with developmental delay and specific features of developmental disabilities. This emphasis helps IDDRC researchers to elucidate the phenotypic variations which are associated with genetic mutations (e.g., chromosomal anomalies, genomic copy number changes, single nucleotide variation and short insertions and deletions [indels]).
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0.913 |