NON-CODING RNAS FOR EPIGENETIC TRANSCRIPTIONAL SILENCING IN PROSTATE CANCER
Zhou Ming-ming
Mount Sinai School Of Medicinecity: New York country: United States (us)
Grant 3R01CA154809-02S1 from National Cancer Institute
Abstract: Prostate cancer afflicts 1 in 4 men by the age of 75 and remains a major public health concern in the United States. Despite some success in disease diagnosis and treatment the molecular parameters that influence the transition from prostatic intraepithelial neoplasia to prostate cancer has remained elusive. The long-term goal of our research is to determine the fundamental molecular mechanisms of epigenetic gene transcription in human biology and disease, particularly human prostate cancer. We focus on the role of Polycomb repressive complexes (PRCs) in transcriptional control of the INK4a/ARF locus, gene products of which are the primary mediators of oncogene-induced senescence. PRC-directed gene silencing is mediated by methylation of histone H3 lysine 27 (H3K27me) at target loci in chromatin that is initiated by the lysine methyltransferase EZH2 of the PRC2 and followed by H3K27me association with the PRC1 by binding to chromobox (CBX) proteins, resulting in chromatin condensation and target gene silencing. Our recent study reveals that the silencing activity of PRC1 for the INK4a/ARF locus requires CBX7 interactions with a non-coding RNA transcript ANRIL (the antisense RNA of INK4a locus) and H3K27me via its conserved chromodomain, highlighting a direct role of long non-coding RNA in epigenetic transcriptional silencing. CBX7 and other key components of PRCs that play a key role in cellular lifespan extension by repressing the INK4a/ARF locus are over-expressed in prostate cancer. We further observed in our study markedly elevated expression of ANRIL, CBX7 and EZH2 and a corresponding decrease in p16Ink4a expression in prostate cancer as compared to normal prostate epithelial cells. However, the molecular mechanism of non-coding RNA in PRC-directed gene silencing is not clear. In this project, we aim to determine the molecular underpinning of the functional interplay between non-coding RNA and H3K27me in gene silencing by the PRCs in normal prostate epithelial cells, as well as during the conversion of prostatic intraepithelial neoplasia into prostate carcinoma using combined chromatin/cell biology and structural/chemical biology methods. We expect that the results emerging from our studies including novel chemical tools will have profound impact on a better understanding of prostate cancer biology and future advance of therapeutic means for prognosis and prevention of human prostate cancer. Non-coding RNA transcripts play a fundamental role in epigenetic control of gene expression in the human genome, but the underlying molecular mechanism has remained elusive. In this project we will investigate how non-coding RNAs function as the molecular circuitry to regulate the epigenetic character of the human genome. The outcome of our study is expected to provide a new understanding of the role of ncRNAs to guide the Polycomb group proteins that govern the epigenome state of human biology of health and disease, particularly prostate cancer
Keywords: Affinity; Age; Antisense RNA; base; Binding (Molecular Function); Binding Sites; Biology; Cancer Biology; CDKN2A gene; Cell Line; Cellular biology; Chemicals; Chromatin; Combinatorial Synthesis; Complex; design; Development; Disease; disease diagnosis; Epigenetic Process; Epithelial; Epithelial Cells; EZH2 gene; Fluorescence Polarization; Functional RNA; Future; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Goals; Health; Histone H3; Homeobox Genes; Human; Human Biology; human disease; Human Genome; in vivo; Investigation; Ligands; Link; Longevity; Lysine; Malignant Epithelial Cell; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; men; Methods; Methylation; Methyltransferase; Molecular; mutant; novel; Oncogenes; Outcome; outcome forecast; Peptides; Physical condensation; Play; Polycomb; PRC1 Protein; Precipitation; Prevention; Process; Prostate; prostate cancer prevention; Prostate carcinoma; Prostatic; Prostatic Intraepithelial Neoplasias; Protein Family; Proteins; public health medicine (field); public health relevance; Recruitment Activity; Repression; Research; RNA; RNA Binding; Role; scaffold; Screening procedure; senescence; Site; small molecule; Staging; Stimulus; Stress; Structure; Structure-Activity Relationship; success; Testing; Therapeutic; tool; Transcript; Transcriptional Regulation; United States
Relevance: Narrative: Non-coding RNA transcripts play a fundamental role in epigenetic control of gene expression in the human genome, but the underlying molecular mechanism has remained elusive. In this project we will investigate how non-coding RNAs function as the molecular circuitry to regulate the epigenetic character of the human genome. The outcome of our study is expected to provide a new understanding of the role of ncRNAs to guide the Polycomb group proteins that govern the epigenome state of human biology of health and disease, particularly prostate cancer
Project start date: 2011-01-01
Project end date: 2015-12-31
Budget start date: 1-JAN-2012
Budget end date: 31-DEC-2012
3R01CA154809-02S1 (2012): $74165
Sponsored Links Excellgen http://Excellgen.com
NON-CODING RNAS FOR EPIGENETIC TRANSCRIPTIONAL SILENCING IN PROSTATE CANCER
Zhou Ming-ming, Associate Professor
Mount Sinai School Of Medicinecity: New York country: United States (us)
Grant 3R01CA154809-01S1 from National Cancer Institute
Abstract: Prostate cancer afflicts 1 in 4 men by the age of 75 and remains a major public health concern in the United States. Despite some success in disease diagnosis and treatment the molecular parameters that influence the transition from prostatic intraepithelial neoplasia to prostate cancer has remained elusive. The long-term goal of our research is to determine the fundamental molecular mechanisms of epigenetic gene transcription in human biology and disease, particularly human prostate cancer. We focus on the role of Polycomb repressive complexes (PRCs) in transcriptional control of the INK4a/ARF locus, gene products of which are the primary mediators of oncogene-induced senescence. PRC-directed gene silencing is mediated by methylation of histone H3 lysine 27 (H3K27me) at target loci in chromatin that is initiated by the lysine methyltransferase EZH2 of the PRC2 and followed by H3K27me association with the PRC1 by binding to chromobox (CBX) proteins, resulting in chromatin condensation and target gene silencing. Our recent study reveals that the silencing activity of PRC1 for the INK4a/ARF locus requires CBX7 interactions with a non-coding RNA transcript ANRIL (the antisense RNA of INK4a locus) and H3K27me via its conserved chromodomain, highlighting a direct role of long non-coding RNA in epigenetic transcriptional silencing. CBX7 and other key components of PRCs that play a key role in cellular lifespan extension by repressing the INK4a/ARF locus are over-expressed in prostate cancer. We further observed in our study markedly elevated expression of ANRIL, CBX7 and EZH2 and a corresponding decrease in p16Ink4a expression in prostate cancer as compared to normal prostate epithelial cells. However, the molecular mechanism of non-coding RNA in PRC-directed gene silencing is not clear. In this project, we aim to determine the molecular underpinning of the functional interplay between non-coding RNA and H3K27me in gene silencing by the PRCs in normal prostate epithelial cells, as well as during the conversion of prostatic intraepithelial neoplasia into prostate carcinoma using combined chromatin/cell biology and structural/chemical biology methods. We expect that the results emerging from our studies including novel chemical tools will have profound impact on a better understanding of prostate cancer biology and future advance of therapeutic means for prognosis and prevention of human prostate cancer
Keywords: Affinity; Age; Antisense RNA; base; Binding (Molecular Function); Binding Sites; Biology; Cancer Biology; CDKN2A gene; Cell Line; Cellular biology; Chemicals; Chromatin; Combinatorial Synthesis; Complex; design; Development; Disease; disease diagnosis; Epigenetic Process; Epithelial; Epithelial Cells; EZH2 gene; Fluorescence Polarization; Functional RNA; Future; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Goals; Health; Histone H3; Homeobox Genes; Human; Human Biology; human disease; Human Genome; in vivo; Investigation; Ligands; Link; Longevity; Lysine; Malignant Epithelial Cell; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; men; Methods; Methylation; Methyltransferase; Molecular; mutant; novel; Oncogenes; Outcome; outcome forecast; Peptides; Physical condensation; Play; Polycomb; PRC1 Protein; Precipitation; Prevention; Process; Prostate; prostate cancer prevention; Prostate carcinoma; Prostatic; Prostatic Intraepithelial Neoplasias; Protein Family; Proteins; public health medicine (field); Recruitment Activity; Repression; Research; RNA; RNA Binding; Role; scaffold; Screening procedure; senescence; Site; small molecule; Staging; Stimulus; Stress; Structure; Structure-Activity Relationship; success; Testing; Therapeutic; tool; Transcript; Transcriptional Regulation; United States
Relevance: Non-coding RNA transcripts play a fundamental role in epigenetic control of gene expression in the human genome, but the underlying molecular mechanism has remained elusive. In this project we will investigate how non-coding RNAs function as the molecular circuitry to regulate the epigenetic character of the human genome. The outcome of our study is expected to provide a new understanding of the role of ncRNAs to guide the Polycomb group proteins that govern the epigenome state of human biology of health and disease, particularly prostate cancer
Project start date: 2011-08-01
Project end date: 2015-12-31
Budget start date: 1-AUG-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-09-199
3R01CA154809-01S1 (2011): $38341
Grants awarded to Zhou Ming-ming
MOLECULAR INTERACTIONS AND REGULATION OF P53
Zhou Ming-ming
Mount Sinai School Of Medicinecity: New York country: United States (us)
Abstract: Site-specific post-translational modifications of human tumor suppressor p53 induced by stress play an important role in the activity of p53 as a transcription factor that regulates cell cycle arrest, senescence or apoptosis. The Iong-term goal of this Project 2, as a part of the PPG, is to seek mechanistic understanding of the molecular interactions and regulation of p53 in human biology and cancer. While multiple acetylation and methylation sites in p53 have been reported, specific effects of individual or combined modifications on p53 activity remain elusive. Preliminary data is presented involving a structure-based functional analysis of p53 supporting the notion that acetylation-induced p53 activation in response to DNA damage is involved in co-activator recruitment and subsequent histone acetylation required for target gene transcriptional activation. Our study specifically supports the notion that p53 recruitment of the co-activator CBP (CREB binding protein) requires association of the CBP bromodomain with p53 at acetylated lys[353] a molecular interaction that is essential for p53-induced transcriptional activation of the cyclin-dependent kinase inhibitor p21, involved in (31 cell cycle arrest. We hypothesize therefore that distinct modifications of p53 including lysine acetylation and merhylation have differential effects on p53 functions in cells. We propose a multifaceted approach to address mechanistic underpinnings of p53 transcriptional activation with the emphasis on the role of post-translational modifications in p53 activation. The specific aims are (1) to elucidate molecular basis of these modification mediated molecular interactions of p53 with co-activators, and to develop small molecule chemical probes with structure-based design to functionally modulate p53 interactions; and (2) to determine the interplay between the co-activators CBP/p300 and p53 C-terminal domain in transcriptional regulation and tumor suppression of p53 using a variety of biochemical and cell biological approaches including the establishment of an in vivo model. The emerging results from our planned studies are expected to yield new mechanistic understanding of post-translational modifications in p53 function. Given the central role of p53 in cancer, these studies will have important implications for the prognosis and treatment of human tumors
Keywords: Acetylation; Address; Affinity; Apoptosis; base; Binding (Molecular Function); Binding Proteins; Biochemical; Biological; Biological Assay; Bromodomain; C-terminal; cancer therapy; Cell Cycle Arrest; Cells; Chemicals; Chromatin; Conflict (Psychology); Confusion; CREB-binding protein; Data; design; DNA Damage; EP300 gene; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Genotoxic Stress; Goals; Health; Histone Acetylation; histone modification; Histones; HTATIP gene; Human; Human Biology; human CREBBP protein; human MDM2 protein; improved; In Vitro; in vivo; in vivo Model; Individual; Joints; Lead; Ligands; Lysine; Malignant Neoplasms; Mediating; Methylation; Modification; Molecular; mouse model; novel; oncoprotein p21; Outcome; outcome forecast; overexpression; p53-binding protein; PCAF gene; Phosphorylation; Play; Post-Translational Protein Processing; Protein p53; Proteins; Recruitment Activity; Regulation; Reliance; Reporting; response; Role; senescence; Site; small molecule; Specificity; Stress; Structure; Testing; TP53 gene; transcription factor; Transcriptional Activation; Transcriptional Regulation; tumor; Tumor Suppression; Ubiquitination
Relevance: This Project aims to understand the molecular interactions and regulation of human tumor suppressor p53 in human biology of health and cancer; and new findings emerging from the planned study will lead to possible novel cancer therapies
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P01CA080058-12_6757 (2011): $214525
NON-CODING RNAS FOR EPIGENETIC TRANSCRIPTIONAL SILENCING IN PROSTATE CANCER
Zhou Ming-ming, Associate Professor
Mount Sinai School Of Medicinecity: New York country: United States (us)
Grant 1R01CA154809-01 from National Cancer Institute
Abstract: Prostate cancer afflicts 1 in 4 men by the age of 75 and remains a major public health concern in the United States. Despite some success in disease diagnosis and treatment the molecular parameters that influence the transition from prostatic intraepithelial neoplasia to prostate cancer has remained elusive. The long-term goal of our research is to determine the fundamental molecular mechanisms of epigenetic gene transcription in human biology and disease, particularly human prostate cancer. We focus on the role of Polycomb repressive complexes (PRCs) in transcriptional control of the INK4a/ARF locus, gene products of which are the primary mediators of oncogene-induced senescence. PRC-directed gene silencing is mediated by methylation of histone H3 lysine 27 (H3K27me) at target loci in chromatin that is initiated by the lysine methyltransferase EZH2 of the PRC2 and followed by H3K27me association with the PRC1 by binding to chromobox (CBX) proteins, resulting in chromatin condensation and target gene silencing. Our recent study reveals that the silencing activity of PRC1 for the INK4a/ARF locus requires CBX7 interactions with a non-coding RNA transcript ANRIL (the antisense RNA of INK4a locus) and H3K27me via its conserved chromodomain, highlighting a direct role of long non-coding RNA in epigenetic transcriptional silencing. CBX7 and other key components of PRCs that play a key role in cellular lifespan extension by repressing the INK4a/ARF locus are over-expressed in prostate cancer. We further observed in our study markedly elevated expression of ANRIL, CBX7 and EZH2 and a corresponding decrease in p16Ink4a expression in prostate cancer as compared to normal prostate epithelial cells. However, the molecular mechanism of non-coding RNA in PRC-directed gene silencing is not clear. In this project, we aim to determine the molecular underpinning of the functional interplay between non-coding RNA and H3K27me in gene silencing by the PRCs in normal prostate epithelial cells, as well as during the conversion of prostatic intraepithelial neoplasia into prostate carcinoma using combined chromatin/cell biology and structural/chemical biology methods. We expect that the results emerging from our studies including novel chemical tools will have profound impact on a better understanding of prostate cancer biology and future advance of therapeutic means for prognosis and prevention of human prostate cancer. Non-coding RNA transcripts play a fundamental role in epigenetic control of gene expression in the human genome, but the underlying molecular mechanism has remained elusive. In this project we will investigate how non-coding RNAs function as the molecular circuitry to regulate the epigenetic character of the human genome. The outcome of our study is expected to provide a new understanding of the role of ncRNAs to guide the Polycomb group proteins that govern the epigenome state of human biology of health and disease, particularly prostate cancer
Keywords: Affinity; Age; Anti-Sense RNA; Antisense RNA; ARF; base; Binding; Binding (Molecular Function); Binding Sites; Biology; Cancer Biology; Cancer Genes; Cancer of Prostate; Cancer-Promoting Gene; Carcinoma Cell; Carcinoma of prostate; CDK4I; CDKN2; CDKN2A; CDKN2A gene; cell biology; Cell Line; Cell Lines, Strains; CellLine; Cellular biology; chemical structure function; Chemicals; Chromatin; CMM2; Combinatorial Synthesis; Combining Site; Complex; condensation; cultured cell line; Cyclin-Dependent Kinase Inhibitor 2A Gene; design; designing; Development; Disease; disease diagnosis; disease/disorder; Disorder; EC 2.1.1; Enhancer of Zeste 2; ENX-1; Epigenetic; Epigenetic Change; Epigenetic Mechanism; Epigenetic Process; Epithelial; Epithelial Cells; EZH1; EZH2; EZH2 gene; Fluorescence Polarization; Forecast of outcome; Functional RNA; Future; Gene Expression; Gene Inactivation; gene product; Gene Products, RNA; Gene Silencing; Gene Transcription; Genes; Genes, CDKN2; Genes, Homeo Box; Genes, Homeobox; Genes, p16; Genes, p16INK4A; Genetic Transcription; Genital System, Male, Prostate; Goals; Health; Histone H3; Homeobox Family Gene; Homeobox Genes; Homeodoamin Gene; Homeotic Genes; HOX gene; Human; Human Biology; human disease; Human Genome; Human Prostate; Human Prostate Gland; Human, General; in vivo; INK4; INK4A; Investigation; L-Lysine; Length of Life; life span; lifespan; Ligands; Link; Longevity; Lysine; Malignant Epithelial Cell; Malignant neoplasm of prostate; Malignant prostatic tumor; Malignant Tumor of the Prostate; Man (Taxonomy); Man, Modern; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; men; men`s; Methods; methylase; Methylation; Methyltransferase; MGC9169; MLM; Molecular; Molecular Interaction; MTS1; MTS1 Genes; mutant; Non-Coding; Non-Coding RNA; novel; Oncogenes; Outcome; outcome forecast; p14ARF; p16INK4 Genes; p16INK4a; Peptides; Physical condensation; Play; Polycomb; Polycomb Repressive Complex 1; PRC1; PRC1 Protein; Precipitation; Prevention; Prevention of Prostate CA; Prevention of Prostate Cancer; Process; Prognosis; Prostate; Prostate CA; Prostate CA Prevention; Prostate Cancer; prostate cancer prevention; Prostate Cancer Prevention; Prostate carcinoma; Prostate Gland; prostate intraepithelial neoplasm; Prostatic; Prostatic Cancer; prostatic cancer, carcinoma; Prostatic carcinoma; Prostatic Gland; Prostatic intraepithelial neoplasia; Prostatic Intraepithelial Neoplasia of the Prostate Gland; Prostatic Intraepithelial Neoplasias; Prostatic Intraepithelial Neoplasms; Protein Family; Protein Methylation; Proteins; Public Health; public health medicine (field); public health relevance; Reactive Site; recruit; Recruitment Activity; Repression; Research; Ribonucleic Acid; RNA; RNA Binding; RNA Expression; RNA, Non-Polyadenylated; Role; scaffold; scaffolding; screening; Screening procedure; screenings; senescence; Site; small molecule; social role; Staging; Stimulus; Stress; Structure; structure function relationship; Structure-Activity Relationship; success; Testing; Therapeutic; tool; TP16; Transcript; Transcription; Transcription Regulation; Transcription, Genetic; Transcriptional Control; Transcriptional Regulation; Transforming Genes; transmethylase; TSG9A; United States
Relevance: Narrative: Non-coding RNA transcripts play a fundamental role in epigenetic control of gene expression in the human genome, but the underlying molecular mechanism has remained elusive. In this project we will investigate how non-coding RNAs function as the molecular circuitry to regulate the epigenetic character of the human genome. The outcome of our study is expected to provide a new understanding of the role of ncRNAs to guide the Polycomb group proteins that govern the epigenome state of human biology of health and disease, particularly prostate cancer
Project start date: 2011-01-01
Project end date: 2015-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-09-199
1R01CA154809-01 (2011): $483031
SMALL MOLECULE LIBRARIES TARGETED TO CBP AND ATTENUATION AFOSB EXPRESSION
Zhou Ming-ming
Mount Sinai School Of Medicinecity: New York country: United States (us)
Grant 5R21DA029963-02 from National Institute On Drug Abuse
Abstract: Addiction is a chronic, relapsing psychiatric disorder characterized by compulsive drug seeking behaviors despite significant physical, mental and social harm to the individuals involved. Progress has been made in elucidating the underlying neuroadaptions that occur in addiction. These involve, in part, a subversion, or hijacking of normal neuronal plasticity associated reward, memory and learning. One of the ways cells respond to external stimuli, including pathological stimuli such as abused psychostimulants, is by altering their pattern of gene expression and one mechanism for this is via epigenetic changes leading to altered patterns of gene transcription. Induction delta FosB is a well characterized neuroplastic event associated with chronic administration of these drugs. Exposure to abused psycostimulants, for example cocaine, leads to histone acetylation of gene promoters, and consequent transcriptional activation, of early response genes, including FosB. Increase in FosB promoter acetylation has been shown to be dependent on CBP (CREB binding protein) dependant histone acetyl transferase (HAT) activity. Thus exposure to drugs of abuses such cocaine and amphetamines have been shown to lead to increase FosB protein expression in cells of the nucleus accumbens. On chronic treatment, a longer lived truncated splice variant of FosB, delta FosB, is expressed and this accumulates in neurons as the transition to an addicted state occurs. Delta FosB is present for an extended period of time after drug is withdrawn and it has thus been implicated as a causative agent in the formation of longer term addictive behaviors and hence propensity for relapse. The key biological hypothesis to be tested by the proposed research is that attenuation of CBP activity by a small molecule inhibitor will reduce acetylation of the FosB gene promoter, which in turn will lower FosB and delta FosB protein expression. High throughput screens of chemical libraries at Mount Sinai have identified two series of hit molecules in a binding assay to CBP bromodomain. Further, these hits have been shown to inhibit CBP mediated HAT activity in cell based reporter assays. These chemical lead series are amenable to exploration and elaboration by parallel synthesis techniques to create libraries of CBP inhibitors. The broad theme of this proposal is to optimize these hits via targeted library synthesis and medicinal chemistry to provide small molecules which will inhibit delta FosB induction via attenuation of CBP HAT activity. These small molecules will function as pharmacological tools to investigate the underlying neuronal adaptations in transition to the addicted state and may provide a novel therapeutic modality for the prevention or reversal of addiction. Addiction is a chronic, relapsing psychiatric disorder characterized by compulsive drug seeking behaviors. Neuronal changes involved in addiction are partly epigenetic and result in a subversion, or hijacking of normal neuronal plasticity associated reward, memory and learning mechanisms in the brain. The theme of this proposal is to identify and optimize small molecules that modulate and attenuate the epigenetic processes associated with addiction; these small molecules will function as pharmacological tools to investigate the underlying neuronal processes in transition to the addicted state and may provide a novel therapeutic modality for the prevention or reversal of addiction
Keywords: Acetylation; Acute; addiction; Addictive Behavior; Address; Affinity; Amphetamines; Animals; Area; Attenuated; attenuation; Back; base; Behavioral; Behavioral Model; Binding (Molecular Function); Biological; Biological Assay; Biological Availability; Brain; Bromodomain; Cell Nucleus; Cells; Chemicals; Chronic; Cocaine; Complex; Computational Technique; CREB-binding protein; Databases; design; Dose; Drug Addiction; drug of abuse; drug seeking behavior; Epigenetic Process; ERG gene; Evaluation; Event; Exposure to; Fluorescence; Fluorescence Spectroscopy; Gene Expression; Genes; Genetic Transcription; Goals; Half-Life; high throughput screening; Histone Acetylation; Histone H3; Histones; human CREBBP protein; Humulus; In Vitro; in vivo; Individual; inhibitor/antagonist; Inhibitory Concentration 50; insight; Investigation; Label; Lead; lead series; Learning; Libraries; Life; Ligand Binding; Ligands; Link; Luciferases; Lysine; Measures; Mediating; Memory; Mental disorders; Methods; Methylation; Modality; Modeling; molecular modeling; Molecular Models; Neuronal Plasticity; Neurons; novel; novel therapeutics; Nucleus Accumbens; Oral; Parents; Pattern; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Phosphorylation; Preparation; Prevention; Process; programs; Promotor (Genetics); Property; protein expression; protein function; Psyche structure; public health relevance; Rattus; Reagent; Recruitment Activity; Relapse; Reporter; Research; response; Rewards; RNA Splicing; Rodent Model; Roentgen Rays; Role; Route; Running; Safety; scaffold; scale up; Screening procedure; Series; small molecule; small molecule libraries; social; Specificity; Staging; stimulant abuse; Stimulus; Structure; Synthesis Chemistry; System; Techniques; Testing; Time; tool; transcription factor; Transcriptional Activation; Transferase; Tryptophan; Ubiquitination; Variant
Relevance: Addiction is a chronic, relapsing psychiatric disorder characterized by compulsive drug seeking behaviors. Neuronal changes involved in addiction are partly epigenetic and result in a subversion, or hijacking of normal neuronal plasticity associated reward, memory and learning mechanisms in the brain. The theme of this proposal is to identify and optimize small molecules that modulate and attenuate the epigenetic processes associated with addiction; these small molecules will function as pharmacological tools to investigate the underlying neuronal processes in transition to the addicted state and may provide a novel therapeutic modality for the prevention or reversal of addiction
Project start date: 2010-08-01
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-DA-10-005
5R21DA029963-02 (2011): $411036
NON-CODING RNAS FOR EPIGENETIC TRANSCRIPTIONAL SILENCING IN PROSTATE CANCER
Zhou Ming-ming
Mount Sinai School Of Medicinecity: New York country: United States (us)
Grant 5R01CA154809-02 from National Cancer Institute
Keywords: Affinity; Age; Antisense RNA; base; Binding (Molecular Function); Binding Sites; Biology; Cancer Biology; CDKN2A gene; Cell Line; Cellular biology; Chemicals; Chromatin; Combinatorial Synthesis; Complex; design; Development; Disease; disease diagnosis; Epigenetic Process; Epithelial; Epithelial Cells; EZH2 gene; Fluorescence Polarization; Functional RNA; Future; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Goals; Health; Histone H3; Homeobox Genes; Human; Human Biology; human disease; Human Genome; in vivo; Investigation; Ligands; Link; Longevity; Lysine; Malignant Epithelial Cell; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; men; Methods; Methylation; Methyltransferase; Molecular; mutant; novel; Oncogenes; Outcome; outcome forecast; Peptides; Physical condensation; Play; Polycomb; PRC1 Protein; Precipitation; Prevention; Process; Prostate; prostate cancer prevention; Prostate carcinoma; Prostatic; Prostatic Intraepithelial Neoplasias; Protein Family; Proteins; public health medicine (field); public health relevance; Recruitment Activity; Repression; Research; RNA; RNA Binding; Role; scaffold; Screening procedure; senescence; Site; small molecule; Staging; Stimulus; Stress; Structure; Structure-Activity Relationship; success; Testing; Therapeutic; tool; Transcript; Transcriptional Regulation; United States
Relevance: Narrative: Non-coding RNA transcripts play a fundamental role in epigenetic control of gene expression in the human genome, but the underlying molecular mechanism has remained elusive. In this project we will investigate how non-coding RNAs function as the molecular circuitry to regulate the epigenetic character of the human genome. The outcome of our study is expected to provide a new understanding of the role of ncRNAs to guide the Polycomb group proteins that govern the epigenome state of human biology of health and disease, particularly prostate cancer
Project start date: 2011-01-01
Project end date: 2015-12-31
Budget start date: 1-JAN-2012
Budget end date: 31-DEC-2012
5R01CA154809-02 (2012): $442232