2007 CAG Triplet Repeat Disorders Gordon Conference
Diane E Merry, Associate Professor
Gordon Research Conferences West Kingston, Ri 02892
Grant 1R13NS058219-01 from National Institute Of Neurological Disorders And Stroke IRG: ZNS1
Abstract: This application requests funding for the 2007 Gordon Research Conference on CAG Triplet Repeat Disorders to be held at Centre Paul Langevin, Aussois, France from May 13-18, 2007. This will be the fourth Gordon Research Conference on CAG repeat disorders; the first was held in 2001 at Mount Holyoke College, the second was held in Il Ciocco, Barga, Italy in May 2003, and the third was held again at Mount Holyoke College in July 2005. During the last decade, the mutation that causes a major group of inherited neurological disorders was found to be a CAG triplet repeat expansion. So far, this group of diseases includes Huntington s disease, the spinocerebellar ataxias 1, 2, 3, 6, 7, and 17, spinal and bulbar muscular atrophy and dentatorubral pallidoluysian atrophy. In each case, the CAG repeat lies within the coding region of the gene and results in an abnormally long polyglutamine tract in the mutant protein. Similarities in the underlying genetics and neuropathology suggest that the mechanisms of pathogenesis share common features. However, these diseases result in different anatomical distributions of the selective loss of neurons in the brain and spinal cord, and therefore the factors that distinguish them also need to be unraveled. Since the identification of the genetic defects, significant insights have been gained into the pathogenesis of these diseases. The field has progressed to the extent that the development of rational therapeutics is not only on the horizon but is already occurring. In order to increase the pace of the basic research, and at the same time set in place the contacts and clinical resources necessary to move the basic science into the clinic, a multidisciplinary research effort is required. It is essential that collaborative projects between scientists from diverse specialties ranging from organic chemistry, fruit fly genetics to clinical neurology can be established. The conference on CAG triplet repeat disorders will gather together young investigators and established senior scientists to deliver provoking lectures on the cutting-edge of science. In keeping with the Gordon Research Conference format, there will be generous time allocated for both structured discussions led by peers and for informal discussions and social interactions to facilitate collaborations. Strong emphasis is placed on training and mentoring of young scientists, and time will be devoted to career issues. All participants will be required to present posters. Priority will be given to women, minorities, and persons with disabilities when selecting participants.
Keywords: genetic disorder, meeting /conference /symposium, nucleic acid repetitive sequence, travel
Project start date: 2007-03-01
Project end date: 2008-02-29
1R13NS058219-01 (2007): $45000
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Diane E Merry
Hormonal Control Of SBMA Pathogenesis
Diane E Merry, Associate Professor
Thomas Jefferson University 201 South 11th St Philadelphia, Pa 191075587
Grant 5R01NS047381-04 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disease affecting motor neurons of the anterior horn and brainstem and caused by the expansion of a polyglutamine tract within the androgen receptor (AR). Recent findings have shown that the disease is initiated by the binding of the AR to its ligand, testosterone or dihydrotestosterone, and its subsequent translocation to the nucleus. This result suggests that the manipulation of the AR ligand, and/or it s binding to the AR, is an important target for therapeutic intervention. Testosterone is metabolized to a more potent form, dihydrotestosterone (DHT), by the enzyme 5-alpha reductase. The neuronal cell type differences in the expression of this enzyme suggest that 5-alpha reductase expression in the motor neurons of the anterior hom and brainstem may contribute to the cell type specificity of SBMA. We propose to test the hypothesis that 5-alpha reductase expression contributes to disease pathogenesis and cell type specificity by modulating its function, using genetic and pharmacologic approaches. Lastly, recent studies indicate that the function of the AR in its normal capacity as a transcription factor is unnecessary for disease pathogenesis, suggesting that nuclear translocation alone is responsible for the onset of disease. We propose to test this hypothesis through the genetic manipulation of AR nuclear translocation in both cell and mouse models of SBMA. Since polyglutamine expansion has been shown to alter the catabolism of the mutant AR, the effect of subcellular localization on AR catabolism of the AR, as well as on its phosphorylation state will be investigated.
Keywords: androgen receptor, degenerative motor system disease, hormone regulation /control mechanism, pathologic process, progressive spinal muscular atrophy, receptor expression, testosterone 5 alpha reductase, biotransformation, dihydrotestosterone, disease /disorder onset, gender difference, gene expression, motor neuron, phosphorylation, protein transport, receptor binding, sensory neuropathy, PC12 cell, behavior test, genetically modified animal, immunocytochemistry, laboratory mouse, male, polymerase chain reaction
Project start date: 2004-07-01
Project end date: 2008-04-30
5R01NS047381-04 (2007): $399718
3R01NS047381-03S1 (2006): $57903
5R01NS047381-03 (2006): $352273
5R01NS047381-02 (2005): $360750
1R01NS047381-01A1 (2004): $354016
POLYGLUTAMINE NEUROTOXICITY IN SBMA
Diane E Merry, Associate Professor
Thomas Jefferson University, 125 S 9th Street, Philadelphia, Pa 19107-5587
Grant 5R01NS032214-16 from National Institute Of Neurological Disorders And Stroke
Abstract: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disease affecting motor neurons of the anterior horn and brainstem and caused by the expansion of a polyglutamine tract within the androgen receptor (AR). Recent findings have shown that the disease is initiated by the binding of the AR to its androgenic ligand, with its subsequent translocation to the nucleus. Within the nucleus, the mutant AR likely functions properly to activate the transcription of target genes; however, fragments of the amino- terminus of the AR accumulate within the nucleus. Substantial evidence indicates that the polyglutamine expansion results in disease, in part, due to its impact on the turnover of the mutant AR. The long-term goals of this proposal are to understand the molecular basis for the inefficient degradation of the expanded polyglutamine AR through the characterization of candidate proteasomal regulators and through a structure/function analysis of AR domains and post-translational modifications . We hypothesize that the normal trafficking and post-translational modifications of the AR are impacted by polyglutamine expansion. Understanding the role of these domains in AR degradative processes and in disease pathogenesis will provide new targets for therapeutic development. Polyglutamine diseases represent a larger family of neurodegenerative diseases characterized by protein misfolding and accumulation; these diseases include Alzheimer´s disease, Huntington disease, Parkinson´s disease and amyotrophic lateral sclerosis (ALS). The research proposed here should lead to a better understanding of the specific pathogenic mechanisms responsible for SBMA; these studies should lead, as well, to a better understanding of these other protein accumulation diseases
Keywords: 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine; 21+ years old; ALS; Adult; Affect; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s Disease; Alzheimers Dementia; Alzheimers disease; Amino Acids; Amyotrophic Lateral Sclerosis; Androgen Receptor; Androgenic Agents; Androgenic Compounds; Androgens; Anterior; Binding; Binding (Molecular Function); Biochemical Genetics; Bone structure of ilium; Brain Stem; Brainstem; CAG repeat; Capping, Receptor; Cell Nucleus; Cell model; Cells; Cellular model; Chemotherapy-Hormones/Steroids; Cytoplasm; DNA; DNA Binding; DNA Binding Interaction; Data; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Deoxyribonucleic Acid; Development; Disease; Disorder; Dysfunction; Endocrine Gland Secretion; Family; Flies; Functional disorder; Funding; Gehrig`s Disease; Gene Targeting; Gene Transcription; Genetic Transcription; Genetic, Biochemical; Goals; Hormones; Horns; Human; Human, Adult; Human, General; Huntington Chorea; Huntington Disease; Huntington`s; Huntington`s Disease; Huntington`s Disease Pathway; Huntingtons Disease; Idiopathic Parkinson Disease; Ilium; Intermediary Metabolism; Investigators; L-Serine; Lead; Length; Lewy Body Parkinson Disease; Ligands; Lou Gehrig Disease; METBL; Man (Taxonomy); Man, Modern; Metabolic Processes; Metabolism; Molecular; Molecular Genetic; Molecular Genetics; Molecular Interaction; Motor Cell; Motor Neuron Disease, Amyotrophic Lateral Sclerosis; Motor Neurons; Nature; Nervous System Diseases; Neurodegenerative Diseases; Neurodegenerative Disorders; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Neurologic Disorders; Neurological Disorders; Nuclear; Nucleus; OH-flutamide; PC-12; PC12 Cells; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson`s; Parkinson`s disease; Parkinsons disease; Pathogenesis; Pb element; Pheochromocytoma Cell Line; Phosphoproteins; Phosphorylation; Phosphorylation Site; Physiopathology; Play; Poly Q; Post-Translational Modifications; Post-Translational Protein Processing; Posttranslational Modifications; Primary Parkinsonism; Primary Senile Degenerative Dementia; Process; Programs (PT); Programs [Publication Type]; Progressive Chorea, Hereditary, Chronic (Huntington); Protein Cleavage; Protein Degradation, Metabolic; Protein Degradation, Regulatory; Protein Modification; Protein Modification, Post-Translational; Protein Phosphorylation; Protein Processing, Post-Translational; Protein Processing, Posttranslational; Protein Turnover; Protein/Amino Acid Biochemistry, Post-Translational Modification; Proteins; Proteolysis; RNA Expression; Receptor Aggregation; Recruitment Activity; Research; Research Personnel; Researchers; Resistance; Role; Serine; Site; Structure; Symptoms; Targetings, Gene; Testing; Therapeutic Androgen; Therapeutic Hormone; Transcription; Transcription Activator; Transcription Coactivator; Transcription Factor Coactivator; Transcription, Genetic; Transcriptional Activator; Transcriptional Activator/Coactivator; Transcriptional Coactivator; Transgenic Mice; Viral Diseases; Virus Diseases; aberrant protein folding; abnormal protein folding; adult human (21+); alpha, alpha, alpha-trifluoro-2-methyl-4`-nitro-m-lactotoluidide; aminoacid; base; dementia of the Alzheimer type; design; designing; disease/disorder; experiment; experimental research; experimental study; fly; gene product; heavy metal Pb; heavy metal lead; hydroxyflutamide; ilium; insight; motoneuron; mouse model; mutant; nervous system disorder; neurodegenerative illness; neurological disease; neuron toxicity; neuronal toxicity; neurotoxicity; novel therapeutic intervention; pathologic protein folding; pathophysiology; pheochromocytoma 12 cell line; poly(glutamine); polyQ; polyglutamine; primary degenerative dementia; programs; protein degradation; protein mis-folding; protein misfolding; recruit; research study; resistant; roscovitine; senile dementia of the Alzheimer type; social role; spinal and bulbar muscular atrophy; therapeutic development; therapeutic target; tool; trafficking; viral infection; virus infection
Project start date: 1994-08-01
Project end date: 2011-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
5R01NS032214-16 (2010): $306900
5R01NS032214-15 (2009): $310000
2R01NS032214-13A2 (2007): $299000
NOVEL THERAPEUTIC APPROACHES IN SBMA
Diane E Merry, Associate Professor
Thomas Jefferson University, 125 S 9th Street, Philadelphia, Pa 19107-5587
Grant 5R21NS057401-02 from National Institute Of Neurological Disorders And Stroke
Abstract: Many neurodegenerative diseases, including spinal and bulbar muscular atrophy (SBMA) and ALS, result from protein misfolding and accumulation due to a variety of both genetic and environmental causes. SBMA is an adult-onset neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR); it is related mechanistically to other neurodegenerative diseases caused by polyglutamine expansion. Although the precise pathway leading to neuronal dysfunction and death is unknown, the evaluation of transgenic mouse and cell models of these diseases have yielded many mechanistic clues. Moreover, our transgenic cell and mouse models of SBMA reproduce the upstream events of polyglutamine-dependent proteolysis and aggregation, making these models highly useful for the analysis of novel therapeutic avenues that affect these upstream events. SBMA stands apart from other polyglutamine diseases in that its onset and progression are androgen-dependent. Our long-term objectives are to use transgenic and cell models that we have developed to evaluate hormone-based therapies, and to identify steps in the metabolism of the expanded AR that are impacted by such compounds. We predict that these studies will reveal new targets, involved in early stages of disease, for therapeutic intervention. To reach these goals, we propose two specific aims 1) To evaluate the efficacy of AR antagonists in modulating disease in SBMA. 2) To determine steps in the pathogenic metabolism of the expanded AR impacted by these compounds, in order to identify new therapeutic targets involved in the altered AR metabolism in SBMA. We anticipate that results from these studies will lead us to new therapies, not only for SBMA, but potentially for other protein misfolding diseases as well. Polyglutamine diseases represent a larger family of neurodegenerative diseases characterized by protein misfolding and accumulation; these diseases include Alzheimer´s disease, Huntington´s disease, Parkinson´s disease and amyotrophic lateral sclerosis (ALS). Therapeutic strategies designed to promote the normal folding and turnover of aberrantly accumulated proteins target upstream events in the pathogenic pathway and are thus, in many ways, independent of the downstream pathogenic mechanisms. The studies proposed here will test novel therapeutic strategies and identify new targets, with the goal of developing therapeutic interventions for both SBMA and other protein accumulation diseases
Keywords: (17Beta)-17-hydroxyandrost-4-en-3-one; 17-beta-Hydroxy-4-Androsten-3-one; 17beta-Hydroxy-5alpha-Androstan-3-One; 17beta-N-(2, 5-bis(trifluoromethyl))phenyl-carbamoyl-4-aza-5alpha-androst-1-en-3-one; 2-Methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide; 21+ years old; 4`-Cyano-alpha, alpha, alpha-trifuloro-3-[(p-fluorophenyl)sulfonyl]-2-methyl-m-lactotoluidide; 4`-Nitro-3`-trifluoromethylisobutyranilide; 4`-cyano-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methyl-3`-(trifluoromethyl)propionanilide; 4-Cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfonyl-2-hydroxy-2-methylpropionyl)aniline; 5 alpha-Dihydrotestosterone; 5-alpha-DHT; 6-D-Leucine-9-(N-ethyl-L-prolinamide)-10-deglycinamide Luteinizing Hormone-Releasing Factor (Pig); ALS; Ablation; Adult; Adverse effects; Affect; Agonist; Alpha, alpha, alpha-trifluoro-2-methy-4`-nitro-m-propionotoluidide; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s Disease; Alzheimers Dementia; Alzheimers disease; Amyotrophic Lateral Sclerosis; Androgen Receptor; Androgenic Agents; Androgenic Compounds; Androgens; Androst-4-en-17beta-ol-3-one; Androstan-3-one, 17-hydroxy-, (5alpha, 17beta)-; Androstanolone; Area; Astra brand of bicalutamide; AstraZeneca brand of bicalutamide; Bicalutamide; Binding; Binding (Molecular Function); Biochemical; Brain; Casodex; Castration; Cell model; Cells; Cellular model; Cessation of life; Chemicals; Chemotherapy-Hormones/Steroids; Clinical Trials; Clinical Trials, Unspecified; Cognitive; Communication, Personal; Cosudex; DHT; DNA Binding; DNA Binding Interaction; Data; Death; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Dehydrogenases; Delta4-androsten-17beta-ol-3-one; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Dihydrotestosterone; Disease; Disorder; Dutasteride; Emotional; Encephalon; Encephalons; Endocrine Gland Secretion; Estrogen Receptors; Evaluation; Event; FLUT; Family; Flutamide; Gehrig`s Disease; Genetic; Goals; Hormones; Human, Adult; Huntington Chorea; Huntington Disease; Huntington`s; Huntington`s Disease; Huntington`s Disease Pathway; Huntingtons Disease; Idiopathic Parkinson Disease; Intermediary Metabolism; Interpersonal Communication; Japan; Knock-out; Knockout; Knowledge of Results; Knowledge of Results (Psychology); LEUP; Lead; Leuprolide; Leuprorelin; Lewy Body Parkinson Disease; Ligands; Lou Gehrig Disease; METBL; Manuscripts; Mediating; Metabolic Processes; Metabolism; Modeling; Molecular Interaction; Motor Cell; Motor Neuron Disease, Amyotrophic Lateral Sclerosis; Motor Neurons; Muscle; Muscle Tissue; N-[4-Cyano-3-(trifluoromethyl)phenyl]3-3[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-propanamide; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Neurodegenerative Diseases; Neurodegenerative Disorders; Neurologic; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Neurological; Neuromuscular Diseases; Neuronal Dysfunction; Niftolid; Niftolide; Onset of illness; Oxidoreductase; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson`s; Parkinson`s disease; Parkinsons disease; Pathology; Pathway interactions; Pb element; Personal Communication; Phase; Poly Q; Post-Translational Modifications; Post-Translational Protein Processing; Posttranslational Modifications; Preparation; Primary Parkinsonism; Primary Senile Degenerative Dementia; Progressive Chorea, Hereditary, Chronic (Huntington); Propanamide, N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4-fluorophenyl)sulfonyl)-2-hydroxy-2-methyl-, (+-)-; Property; Property, LOINC Axis 2; Protein Cleavage; Protein Modification; Protein Modification, Post-Translational; Protein Processing, Post-Translational; Protein Processing, Posttranslational; Protein/Amino Acid Biochemistry, Post-Translational Modification; Proteins; Proteolysis; Reductases; Staging; Stanolone; Surgical Castration; Symptoms; Testing; Testosterone; Therapeutic; Therapeutic Androgen; Therapeutic Androstanolone; Therapeutic Effect; Therapeutic Hormone; Therapeutic Intervention; Therapeutic Testosterone; Toxic effect; Toxicities; Trans-Testosterone; Transgenic Mice; Transgenic Organisms; Treatment Side Effects; United States National Institutes of Health; Zeneca brand of bicalutamide; aberrant protein folding; abnormal protein folding; adult human (21+); base; clinical investigation; dementia of the Alzheimer type; design; designing; disease onset; disease/disorder; disorder onset; efficacy testing; gene product; genetic manipulation; heavy metal Pb; heavy metal lead; inhibitor; inhibitor/antagonist; intervention therapy; knowledge of results; motoneuron; mouse model; mutant; myoneural disorder; neurodegenerative illness; neuromuscular disorder; new therapeutic target; new therapeutics; next generation therapeutics; novel; novel therapeutic intervention; novel therapeutics; pathologic protein folding; pathway; poly(glutamine); polyQ; polyglutamine; prevent; preventing; primary degenerative dementia; protein mis-folding; protein misfolding; public health relevance; receptor binding; senile dementia of the Alzheimer type; side effect; spinal and bulbar muscular atrophy; therapy adverse effect; transgenic; treatment adverse effect
Project start date: 2009-06-05
Project end date: 2011-05-31
Budget start date: 1-JUN-2010
Budget end date: 31-MAY-2011
PFA/PA: PAR-06-189
5R21NS057401-02 (2010): $231750
INHIBITING THE ANDROGEN RECEPTOR N/C INTERACTION TO TREAT SBMA
Diane E Merry, Associate Professor
Thomas Jefferson University, 125 S 9th Street, Philadelphia, Pa 19107-5587
Grant 1R21NS071032-01 from National Institute Of Neurological Disorders And Stroke
Abstract: Many neurodegenerative diseases, including spinal and bulbar muscular atrophy (SBMA) and ALS, result from protein misfolding and accumulation due to a variety of both genetic and environmental causes. SBMA is an adult-onset neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR); it is related mechanistically to other neurodegenerative diseases caused by polyglutamine expansion. Although the precise pathway leading to neuronal dysfunction and death is unknown, the evaluation of transgenic mouse and cell models of these diseases have yielded many mechanistic clues. Our transgenic cell and mouse models of SBMA reproduce the proximate events of polyglutamine-dependent proteolysis and aggregation, making these models highly useful for the analysis of novel therapeutic avenues that affect these upstream events. SBMA stands apart from other polyglutamine diseases in that its onset and progression are androgen- dependent. Our preliminary studies in our cell models of SBMA indicate that a structural change in the AR that occurs upon androgen binding and that involves an interdomain interaction between the amino- (N-) and carboxyl- (C-) terminal regions is required for mutant AR aggregation and toxicity. Our long-term objectives are to use our transgenic mouse and cell models to evaluate the therapeutic efficacy of novel AR ligands that prevent the AR N/C interaction. We predict that these studies will reveal the details of which of these ligands is most effective and allow us to further develop this subclass of ligands for therapeutic intervention. To reach these goals, we propose two specific aims 1) To evaluate the efficacy of SARMs that prevent the N/C interaction in modulating AR aggregation and toxicity in two cell models of SBMA, and to evaluate the transcriptional function of the mutant AR upon SARM binding; 2) To carry out preclinical testing of the most effective SARMs in our transgenic mouse model of SBMA. We anticipate that results from these studies will lead us to new therapies for SBMA and will open a novel investigational door for other polyglutamine diseases as well. Polyglutamine diseases represent a larger family of neurodegenerative diseases characterized by protein misfolding and accumulation; these diseases include Alzheimer´s disease, Huntington´s disease, Parkinson´s disease and amyotrophic lateral sclerosis (ALS). We are developing a therapeutic strategy designed to prevent the abnormal folding and accumulation of mutant protein, which represents an upstream event in the pathogenic pathway. The studies proposed here will test novel therapeutic compounds that bind to the mutant protein, allow its normal function, but prevent the formation of a toxic conformation; this strategy, if successful, should also be relevant to other neurodegenerative diseases
Keywords: 21+ years old; 4`-Cyano-alpha, alpha, alpha-trifuloro-3-[(p-fluorophenyl)sulfonyl]-2-methyl-m-lactotoluidide; 4`-cyano-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methyl-3`-(trifluoromethyl)propionanilide; 4-Cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfonyl-2-hydroxy-2-methylpropionyl)aniline; ALS; Ablation; Abscission; Address; Adult; Adverse effects; Affect; Agonist; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s Disease; Alzheimers Dementia; Alzheimers disease; Amyotrophic Lateral Sclerosis; Androgen Receptor; Androgenic Agents; Androgenic Compounds; Androgens; Animals; Astra brand of bicalutamide; AstraZeneca brand of bicalutamide; Bicalutamide; Binding; Binding (Molecular Function); Bioavailability; Biochemical; Biologic Availability; Biological Availability; C-terminal; Capping, Receptor; Casodex; Castration; Cell Death; Cell model; Cells; Cellular model; Cessation of life; Clinical Trials; Clinical Trials, Unspecified; Cosudex; Data; Death; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Disease; Disorder; Drug Kinetics; Dysfunction; Evaluation; Event; Excision; Exhibits; Expression Profiling; Expression Signature; Extirpation; Family; Functional disorder; Gehrig`s Disease; Gene Transcription; Genetic; Genetic Transcription; Goals; Hormonal; Human, Adult; Huntington Chorea; Huntington Disease; Huntington`s; Huntington`s Disease; Huntington`s Disease Pathway; Huntingtons Disease; Idiopathic Parkinson Disease; Intermediary Metabolism; Investigation; Lead; Lewy Body Parkinson Disease; Ligands; Lou Gehrig Disease; METBL; Mammals, Mice; Medulla Spinalis; Metabolic Processes; Metabolism; Methods; Mice; Modeling; Molecular Configuration; Molecular Conformation; Molecular Fingerprinting; Molecular Interaction; Molecular Profiling; Molecular Stereochemistry; Motor; Motor Cell; Motor Neuron Disease, Amyotrophic Lateral Sclerosis; Motor Neurons; Murine; Mus; N-[4-Cyano-3-(trifluoromethyl)phenyl]3-3[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-propanamide; N-terminal; NH2-terminal; NIH; NRVS-SYS; National Institutes of Health; National Institutes of Health (U.S.); Nervous System; Nervous system structure; Neurodegenerative Diseases; Neurodegenerative Disorders; Neurologic Body System; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Neurologic Organ System; Neuromuscular Diseases; Neuronal Dysfunction; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson`s; Parkinson`s disease; Parkinsons disease; Pathology; Pathway interactions; Pb element; Pharmacokinetics; Phenotype; Physiologic Availability; Physiopathology; Pilot Projects; Poly Q; Post-Translational Modifications; Post-Translational Protein Processing; Posttranslational Modifications; Preclinical Testing; Prevention; Primary Parkinsonism; Primary Senile Degenerative Dementia; Progressive Chorea, Hereditary, Chronic (Huntington); Propanamide, N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4-fluorophenyl)sulfonyl)-2-hydroxy-2-methyl-, (+-)-; Property; Property, LOINC Axis 2; Protein Cleavage; Protein Modification; Protein Modification, Post-Translational; Protein Processing, Post-Translational; Protein Processing, Posttranslational; Protein/Amino Acid Biochemistry, Post-Translational Modification; Proteins; Proteolysis; RNA Expression; Receptor Aggregation; Removal; Spinal Cord; Staging; Surgical Castration; Surgical Removal; Symptoms; Testing; Therapeutic; Therapeutic Androgen; Therapeutic Intervention; Toxic effect; Toxicities; Toxicity Testing; Toxicity Tests; Transcription; Transcription, Genetic; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Treatment Side Effects; United States National Institutes of Health; Universities; Work; Zeneca brand of bicalutamide; aberrant protein folding; abnormal protein folding; adult human (21+); base; bioavailability of drug; clinical investigation; conformation; conformational state; dementia of the Alzheimer type; design; designing; disease/disorder; dosage; gene product; heavy metal Pb; heavy metal lead; intervention therapy; molecuar profile; molecular signature; motoneuron; mouse model; mutant; myoneural disorder; necrocytosis; neurodegenerative illness; neuromuscular disorder; neuron cell death; neuron loss; neuronal cell death; neuronal loss; neuropathology; neuroprotection; new therapeutics; next generation therapeutics; novel; novel therapeutics; pathologic protein folding; pathophysiology; pathway; pilot study; poly(glutamine); polyQ; polyglutamine; pre-clinical; preclinical; prevent; preventing; primary degenerative dementia; protein mis-folding; protein misfolding; public health relevance; receptor function; resection; selective androgen receptor modulator; senile dementia of the Alzheimer type; side effect; spinal and bulbar muscular atrophy; therapeutic efficacy; therapeutically effective; therapy adverse effect; transgenic; treatment adverse effect
Relevance: Polyglutamine diseases represent a larger family of neurodegenerative diseases characterized by protein misfolding and accumulation; these diseases include Alzheimer´s disease, Huntington´s disease, Parkinson´s disease and amyotrophic lateral sclerosis (ALS). We are developing a therapeutic strategy designed to prevent the abnormal folding and accumulation of mutant protein, which represents an upstream event in the pathogenic pathway. The studies proposed here will test novel therapeutic compounds that bind to the mutant protein, allow its normal function, but prevent the formation of a toxic conformation; this strategy, if successful, should also be relevant to other neurodegenerative diseases
Project start date: 2010-07-07
Project end date: 2012-06-30
Budget start date: 7-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PAR-08-228
1R21NS071032-01 (2010): $193375
Sponsored Links Excellgen http://Excellgen.com
NOVEL THERAPEUTIC APPROACHES IN SBMA
Diane E Merry, Associate Professor
Thomas Jefferson University, 125 S 9th Street, Philadelphia, Pa 19107-5587
Grant 1R21NS057401-01A2 from National Institute Of Neurological Disorders And Stroke
Abstract: Many neurodegenerative diseases, including spinal and bulbar muscular atrophy (SBMA) and ALS, result from protein misfolding and accumulation due to a variety of both genetic and environmental causes. SBMA is an adult-onset neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR); it is related mechanistically to other neurodegenerative diseases caused by polyglutamine expansion. Although the precise pathway leading to neuronal dysfunction and death is unknown, the evaluation of transgenic mouse and cell models of these diseases have yielded many mechanistic clues. Moreover, our transgenic cell and mouse models of SBMA reproduce the upstream events of polyglutamine-dependent proteolysis and aggregation, making these models highly useful for the analysis of novel therapeutic avenues that affect these upstream events. SBMA stands apart from other polyglutamine diseases in that its onset and progression are androgen-dependent. Our long-term objectives are to use transgenic and cell models that we have developed to evaluate hormone-based therapies, and to identify steps in the metabolism of the expanded AR that are impacted by such compounds. We predict that these studies will reveal new targets, involved in early stages of disease, for therapeutic intervention. To reach these goals, we propose two specific aims 1) To evaluate the efficacy of AR antagonists in modulating disease in SBMA. 2) To determine steps in the pathogenic metabolism of the expanded AR impacted by these compounds, in order to identify new therapeutic targets involved in the altered AR metabolism in SBMA. We anticipate that results from these studies will lead us to new therapies, not only for SBMA, but potentially for other protein misfolding diseases as well. Polyglutamine diseases represent a larger family of neurodegenerative diseases characterized by protein misfolding and accumulation; these diseases include Alzheimer´s disease, Huntington´s disease, Parkinson´s disease and amyotrophic lateral sclerosis (ALS). Therapeutic strategies designed to promote the normal folding and turnover of aberrantly accumulated proteins target upstream events in the pathogenic pathway and are thus, in many ways, independent of the downstream pathogenic mechanisms. The studies proposed here will test novel therapeutic strategies and identify new targets, with the goal of developing therapeutic interventions for both SBMA and other protein accumulation diseases
Keywords: (17Beta)-17-hydroxyandrost-4-en-3-one; 17-beta-Hydroxy-4-Androsten-3-one; 17beta-Hydroxy-5alpha-Androstan-3-One; 17beta-N-(2, 5-bis(trifluoromethyl))phenyl-carbamoyl-4-aza-5alpha-androst-1-en-3-one; 2-Methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide; 21+ years old; 4`-Cyano-alpha, alpha, alpha-trifuloro-3-[(p-fluorophenyl)sulfonyl]-2-methyl-m-lactotoluidide; 4`-Nitro-3`-trifluoromethylisobutyranilide; 4`-cyano-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methyl-3`-(trifluoromethyl)propionanilide; 4-Cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfonyl-2-hydroxy-2-methylpropionyl)aniline; 5 alpha-Dihydrotestosterone; 5-alpha-DHT; 6-D-Leucine-9-(N-ethyl-L-prolinamide)-10-deglycinamide Luteinizing Hormone-Releasing Factor (Pig); ALS; Ablation; Adult; Adverse effects; Affect; Agonist; Alpha, alpha, alpha-trifluoro-2-methy-4`-nitro-m-propionotoluidide; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s Disease; Alzheimers Dementia; Alzheimers disease; Amyotrophic Lateral Sclerosis; Androgen Receptor; Androgenic Agents; Androgenic Compounds; Androgens; Androst-4-en-17beta-ol-3-one; Androstan-3-one, 17-hydroxy-, (5alpha, 17beta)-; Androstanolone; Area; Astra brand of bicalutamide; AstraZeneca brand of bicalutamide; Bicalutamide; Binding; Binding (Molecular Function); Biochemical; Brain; Casodex; Castration; Cell model; Cells; Cellular model; Cessation of life; Chemicals; Chemotherapy-Hormones/Steroids; Clinical Trials; Clinical Trials, Unspecified; Cognitive; Communication, Personal; Cosudex; DHT; DNA Binding; DNA Binding Interaction; Data; Death; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Dehydrogenases; Delta4-androsten-17beta-ol-3-one; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Dihydrotestosterone; Disease; Disorder; Dutasteride; Emotional; Encephalon; Encephalons; Endocrine Gland Secretion; Estrogen Receptors; Evaluation; Event; FLUT; Family; Flutamide; Gehrig`s Disease; Genetic; Goals; Hormones; Human, Adult; Huntington Chorea; Huntington Disease; Huntington`s; Huntington`s Disease; Huntington`s Disease Pathway; Huntingtons Disease; Idiopathic Parkinson Disease; Intermediary Metabolism; Interpersonal Communication; Japan; Knock-out; Knockout; Knowledge of Results; Knowledge of Results (Psychology); LEUP; Lead; Leuprolide; Leuprorelin; Lewy Body Parkinson Disease; Ligands; Lou Gehrig Disease; METBL; Manuscripts; Mediating; Metabolic Processes; Metabolism; Mice, Transgenic; Modeling; Molecular Interaction; Motor Cell; Motor Neuron Disease, Amyotrophic Lateral Sclerosis; Motor Neurons; Muscle; Muscle Tissue; N-[4-Cyano-3-(trifluoromethyl)phenyl]3-3[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-propanamide; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Neurodegenerative Diseases; Neurodegenerative Disorders; Neurologic; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Neurological; Neuromuscular Diseases; Neuronal Dysfunction; Niftolid; Niftolide; Onset of illness; Oxidoreductase; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson`s; Parkinson`s disease; Parkinsons disease; Pathology; Pathway interactions; Pb element; Personal Communication; Phase; Poly Q; Post-Translational Modifications; Post-Translational Protein Processing; Posttranslational Modifications; Preparation; Primary Parkinsonism; Primary Senile Degenerative Dementia; Progressive Chorea, Hereditary, Chronic (Huntington); Propanamide, N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4-fluorophenyl)sulfonyl)-2-hydroxy-2-methyl-, (+-)-; Property; Property, LOINC Axis 2; Protein Cleavage; Protein Modification; Protein Modification, Post-Translational; Protein Processing, Post-Translational; Protein Processing, Posttranslational; Protein/Amino Acid Biochemistry, Post-Translational Modification; Proteins; Proteolysis; Reductases; Staging; Stanolone; Surgical Castration; Symptoms; Testing; Testosterone; Therapeutic; Therapeutic Androgen; Therapeutic Androstanolone; Therapeutic Effect; Therapeutic Hormone; Therapeutic Intervention; Therapeutic Testosterone; Toxic effect; Toxicities; Trans-Testosterone; Transgenic Mice; Transgenic Organisms; Treatment Side Effects; United States National Institutes of Health; Zeneca brand of bicalutamide; aberrant protein folding; abnormal protein folding; adult human (21+); base; clinical investigation; dementia of the Alzheimer type; design; designing; disease onset; disease/disorder; disorder onset; efficacy testing; gene product; genetic manipulation; heavy metal Pb; heavy metal lead; inhibitor; inhibitor/antagonist; intervention therapy; knowledge of results; motoneuron; mouse model; mutant; myoneural disorder; neurodegenerative illness; neuromuscular disorder; new therapeutic target; new therapeutics; next generation therapeutics; novel; novel therapeutic intervention; novel therapeutics; pathologic protein folding; pathway; poly(glutamine); polyQ; polyglutamine; prevent; preventing; primary degenerative dementia; protein mis-folding; protein misfolding; public health relevance; receptor binding; senile dementia of the Alzheimer type; side effect; spinal and bulbar muscular atrophy; therapy adverse effect; transgenic; treatment adverse effect
Project start date: 2009-06-05
Project end date: 2011-05-31
Budget start date: 5-JUN-2009
Budget end date: 31-MAY-2010
PFA/PA: PAR-06-189
1R21NS057401-01A2 (2009): $193125
INTERACTIONS OF ANDROGEN RECEPTOR POLYGLUTAMINE TRACT
Diane E Merry, Associate Professor
University Of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104
Grant 1R29NS036248-01 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: Applicant s ) Spinal and bulbar muscular atrophy is an adult-onset neurodegenerative disease characterized by muscle weakness, atrophy, and fasciculations. It is a member of a growing family of neurodegenerative diseases caused by the expansion of a CAG repeat that encodes a poly-glutamine tract within the associated protein coding sequence. Our hypothesis is that the neurodegeneration seen in these diseases results from the gain of a toxic function in the encoded protein due to the presence of the poly-glutamine tract, and that this toxic effect is mediated by specific protein-protein interactions. This project proposes to identify and isolate proteins (and their associated cDNAs) that interact with androgen receptor containing different length poly-glutamine tracts. This will be done in two ways. First, we will use a yeast two-hybrid system to identify proteins that interact with the amino terminal region of the androgen receptor containing 24, 45, or 66 glutamine repeats. We will also use this system to characterize the dependence of interactions on the length of the poly-glutamine tract. We expect that for an interaction to play a role in the pathogenic process, it should be affected in some way by the length of the glutamine repeat. Second, we will screen a lambda phage expression library using radioactively-labeled androgen receptor proteins of different repeat lengths purified from bacteria. This method will allow us to differentially screen libraries using full-length androgen receptor containing different length poly-glutamine tracts. This system will also be exploited for characterization of binding properties of proteins identified through either approach. Lastly, we will characterize the physiologic relevance of protein interactions identified through these screens using cell culture and transgenic model systems that we have developed. The results of these experiments should provide insights into the molecular mechanism by which expanded poly-glutamine tracts become toxic to neurons, and may consequently provide targets for therapeutic intervention. In addition, understanding androgen receptor protein interactions in neurons will increase our understanding of the role of steroid hormone receptors in these cells.
Keywords: androgen receptor, binding protein, degenerative motor system disease, neuromuscular disorder, protein structure /function, receptor binding, brain, chemical chain length, cytotoxicity, genetic library, glutamine, intermolecular interaction, molecular site, neurogenetics, neuron, nucleic acid repetitive sequence, protein sequence, bacteriophage lambda, tissue /cell culture, transgenic animal, yeast two hybrid system
Project start date: 1997-04-01
Project end date: 2002-01-31
1R29NS036248-01 (1997): $115982
5R29NS036248-06 (2001): $112175
5R29NS036248-05 (2000): $108995
7R29NS036248-04 (1999): $34730
5R29NS036248-03 (1999): $71223
5R29NS036248-02 (1998): $110788
Polyglutamine Neurotoxicity In SBMA
Diane E Merry, Associate Professor
Thomas Jefferson University 201 South 11th St Philadelphia, Pa 191075587
Grant 5R01NS032214-12 from National Institute Of Neurological Disorders And Stroke IRG: ZNS1
Keywords: androgen receptor, cellular pathology, degenerative motor system disease, neuropathology, neurotoxicology, polyglutamate, gene expression, gene mutation, genetic regulatory element, motor neuron, neural degeneration, neurotoxin, protease inhibitor, sex linked trait, Drosophilidae, RNase protection assay, genetically modified animal, immunocytochemistry, in situ hybridization, laboratory mouse, northern blotting, polymerase chain reaction, subtraction hybridization, tissue /cell culture, western blotting
Project start date: 1994-08-01
Project end date: 2007-04-30
5R01NS032214-12 (2005): $318000
5R01NS032214-11 (2004): $318000
5R01NS032214-10 (2003): $318000
Sponsored Links Excellgen http://Excellgen.com
5R01NS032214-09 (2002): $318000
2R01NS032214-08A1 (2001): $313870
3R01NS032214-08A1S1 (2001): $50000