An in vivo screen for biological and chemical regulators of mammalial PDEs
An in vivo screen for biological and chemical regulators of mammalial PDEs
批准号:
7337165
负责人:
CHARLES S. HOFFMAN
金额:
$19.43万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
已结题
起止时间:
2007-01-01 至 2009-06-30
关键词:
Adenylate CyclaseAdverse effectsAllergic rhinitisAlzheimer&aposs DiseaseBehaviorBiologicalBiological AssayBiological ProcessCandidate Disease GeneCardiacCellsChemicalsConditionCyclic AMPCyclic GMPCystic FibrosisDetectionDevelopmentDiseaseDot ImmunoblottingEngineeringEnvironmentEnzymesFacility Construction Funding CategoryFamilyFission YeastFluorescenceFutureGenesGenetic TranscriptionGlucoseGoalsGrowthHematologic NeoplasmsHuntington DiseaseIndividualIsoenzymesKidney DiseasesLeadLibrariesLungMalignant NeoplasmsMeasurementMeasuresMental DepressionMultiple SclerosisMusMutationPDE4A4PDE4BPathway interactionsPharmacotherapyPhenotypePhosphodiesterase InhibitorsPilot ProjectsPreclinical Drug EvaluationProcessPsoriasisRNA SplicingRangeRateRegulationRelative (related person)ReporterRepressionResearch PersonnelResistanceRheumatoid ArthritisRoleSchizophreniaScreening procedureSecond Messenger SystemsSignal PathwaySignal TransductionSpecificitySystemTherapeuticTherapeutic IndexThinkingTissuesTreatment EfficacyVariantWorkYeastsbasecDNA Librarycell growthdiethylstilbestrol monophosphateexpression vectorhigh throughput screeninghuman tissuein vitro Assayin vivoinhibitor/antagonistmembernext generationnovelphosphoric diester hydrolaseprogramsresearch studyresponsesecond messengersmall molecule libraries
中文摘要
许多生物学过程都受到细胞感知环境中分子并创造
细胞内信号以实现适当的生物反应。一个主要的信号通路涉及
调节cAMP水平,这是腺苷酸环化酶和cAMP合成的功能
cAMP磷酸二酯酶(PDE)的破坏。在裂殖酵母,粟酒裂殖酵母,cAMP
水平由包括单个PDE基因的葡萄糖信号传导途径调节。我们已经开发
报告构建体,其赋予反映细胞的细胞内cAMP水平的生长表型。我们
我建议将哺乳动物PDE基因引入我们的菌株,这样生长行为将是一个功能,
PDE活动。我们将使用这些菌株来实现以下两个目标。1)我们将进行高
用于特定PDE的化学抑制剂的通量筛选。利用表达各种鼠源性
PDE(4A,4B,8A,8B),我们希望能够识别非特异性和特异性抑制剂。值得注意的是,
已知的PDE8特异性抑制剂,因此难以确定PDES酶在
各种生物过程。2)我们将利用这些菌株筛选一个cDNA文库,
靶PDE并鉴定表达这些激活剂的组织。同时表达两种蛋白的菌株
激活剂和靶PDE将进行化学文库筛选,以寻找抑制PDE的化合物。
激活剂,而不是PDE本身。因为这些激活剂可以在其中表达激活剂的组织亚组中表达,
当发现PDE时,靶向激活剂的化合物可以对PDE活性提供更组织特异性的作用,
因此提供了治疗益处,而副作用比
直接瞄准PDE目前有广泛的疾病正在用PDE治疗
抑制剂,或被认为适合于用PDE抑制剂治疗。因此发展
这种鉴定PDE的化学和生物调节剂的体内平台具有鉴定
用于治疗心脏、肺和肾脏疾病的下一代PDE相关药物,
以及某些癌症、囊性纤维化、多发性硬化、类风湿性关节炎、亨廷顿氏病,
过敏性鼻炎、牛皮癣、精神分裂症、阿尔茨海默病和抑郁症。
英文摘要
Many biological processes are regulated by a cell's ability to sense molecules in its environment and create
an intracellular signal to effect an appropriate biological response. One major signaling pathway involves the
regulation of cAMP levels, which is a function of cAMP synthesis by adenylate cyclases and cAMP
destruction by cAMP phosphodiesterases (PDE). In the fission yeast, Schizosaccharomyces pombe, cAMP
levels are regulated by a glucose signaling pathway that includes a single PDE gene. We have developed
reporter constructs,which confer growth phenotypes that reflect the cell's intracellular cAMP level. We
propose to introduce mammalian PDE genes into our strains, such that the growth behavior will be a function
of PDE activity. We will use such strains to carry out the following two aims. 1) We will conduct high
throughput screening for chemical inhibitors of specific PDEs. Utilizing strains expressing various murine
PDEs (4A, 4B, 8A, 8B), we expect to identify both nonspecific and specific inhibitors. Of note, there are no
known PDE8-specific inhibitors, thus making it difficult to determine the relative role of PDES enzymes in
various biological processes. 2) We will use these strains to screen a cDNA library for biological activatorsof
the target PDE and identify the tissues in which these activatorsare expressed. Strains expressing both the
activator and the target PDE will be subjected to chemical library screens for compounds that inhibit the
activator, rather than the PDE itself. As these activators may be expressed in a subset of tissues in which the
PDE is found, compounds that target the activator may provide a more tissue-specific effect on PDE activity,
and thus provide a therapeutic benefit with less of a side-effect than would be possible for compounds that
target the PDE directly. There is a broad range of diseases that are currently being treated with PDE
inhibitors, or are thought to be amenable to treatment with PDE inhibitors. Therefore, the development of
this in vivo platform to identify chemical and biological regulators of PDEs has the potential of identifying the
next generation of PDE-related Pharmaceuticalsfor the treatment of cardiac, pulmonary, and renal diseases,
as well as certain cancers, cystic fibrosis, multiple sclerosis, rheumatoid arthritis, Huntington's Disease,
allergic rhinitis, psoriasis, schizophrenia, Alzheimer's disease and depression.
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DOI:
10.3389/fphar.2021.833156
发表时间:
2021
期刊:
Frontiers in pharmacology
影响因子:
5.6
作者:
[Hoffman CS]
通讯作者:
Hoffman CS
DOI:
10.1371/journal.pone.0071279
发表时间:
2013
期刊:
PloS one
影响因子:
3.7
作者:
[Demirbas D, Wyman AR, Shimizu-Albergine M, Cakici O, Beavo JA, Hoffman CS]
通讯作者:
Hoffman CS
Fission yeast-based high-throughput screens for PKA pathway inhibitors and activators.
基于裂变酵母的 PKA 途径抑制剂和激活剂高通量筛选。
DOI:
10.1007/978-1-4939-2269-7_6
发表时间:
2015
期刊:
Methods in molecular biology (Clifton, N.J.)
影响因子:
--
作者:
[deMedeiros,AnaSantos, Kwak,Grace, Vanderhooft,Jordan, Rivera,Sam, Gottlieb,Rachel, Hoffman,CharlesS]
通讯作者:
Hoffman,CharlesS
DOI:
10.1177/1087057110362100
发表时间:
2010-04
期刊:
Journal of biomolecular screening
影响因子:
--
作者:
[Alaamery MA, Wyman AR, Ivey FD, Allain C, Demirbas D, Wang L, Ceyhan O, Hoffman CS]
通讯作者:
Hoffman CS
Methods to Assess Phosphodiesterase and/or Adenylyl Cyclase Activity Via Heterologous Expression in Fission Yeast.
通过裂殖酵母中的异源表达评估磷酸二酯酶和/或腺苷酸环化酶活性的方法。
DOI:
10.1007/978-1-0716-2245-2_6
发表时间:
2022
期刊:
Methods in molecular biology (Clifton, N.J.)
影响因子:
--
作者:
[Domin,Marek, Hoffman,CharlesS]
通讯作者:
Hoffman,CharlesS
Pharmacologic Inhibition of PDE11A for Age-Related Memory Disorders
-
批准号:10260396
-
项目类别:
-
资助金额:$73.78万
-
财政年份:2020
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
Pharmacologic Inhibition of PDE11A for Age-Related Memory Disorders
-
批准号:10617261
-
项目类别:
-
资助金额:$72.6万
-
财政年份:2020
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
Pharmacologic Inhibition of PDE11A for Age-Related Memory Disorders
-
批准号:10401488
-
项目类别:
-
资助金额:$73.15万
-
财政年份:2020
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
ADENYLATE CYCLASE-ASSOCIATED COMPLEXES IN SCHIZOSACCHAROMYCES POMBE
-
批准号:7602230
-
项目类别:
-
资助金额:$0.62万
-
财政年份:2007
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
An in vivo screen for biological and chemical regulators of mammalial PDEs
-
批准号:7187461
-
项目类别:
-
资助金额:$23.29万
-
财政年份:2007
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
ADENYLATE CYCLASE-ASSOCIATE COMPLEXES IN SCHIZOSACCHAROMYCES POMBE
-
批准号:7420704
-
项目类别:
-
资助金额:$0.29万
-
财政年份:2006
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
ADENYLATE CYCLASE-ASSOCIATE COMPLEXES IN S. POMBE
-
批准号:6979642
-
项目类别:
-
资助金额:$0.36万
-
财政年份:2004
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
CHARACTERIZATION OF THE S POMBE CAMP SIGNAL PATHWAY
-
批准号:3468475
-
项目类别:
-
资助金额:$9.83万
-
财政年份:1991
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
Characterization of the S. Pombe cAMP Pathway
-
批准号:6732673
-
项目类别:
-
资助金额:$30.6万
-
财政年份:1991
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
S POMBE CAMP SIGNAL PATHWAY
-
批准号:2183728
-
项目类别:
-
资助金额:$11.13万
-
财政年份:1991
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
S POMBE CAMP SIGNAL PATHWAY
-
批准号:2183731
-
项目类别:
-
资助金额:$18.35万
-
财政年份:1991
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
CHARACTERIZATION OF THE S POMBE CAMP SIGNAL PATHWAY
-
批准号:3468476
-
项目类别:
-
资助金额:$10.42万
-
财政年份:1991
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
Characterization of the S. Pombe cAMP Pathway
-
批准号:7020989
-
项目类别:
-
资助金额:$10.3万
-
财政年份:1991
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
Characterization of the S. Pombe cAMP Pathway
-
批准号:6519454
-
项目类别:
-
资助金额:$30.43万
-
财政年份:1991
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
S POMBE CAMP SIGNAL PATHWAY
-
批准号:2734701
-
项目类别:
-
资助金额:$31.13万
-
财政年份:1991
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
S POMBE CAMP SIGNAL PATHWAY
-
批准号:6018845
-
项目类别:
-
资助金额:$32.23万
-
财政年份:1991
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
Characterization of the S. Pombe cAMP Pathway
-
批准号:6326877
-
项目类别:
-
资助金额:$30.6万
-
财政年份:1991
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
TRANSCRIPTIONAL REGULATION OF THE S POMBE FBPL GENE
-
批准号:2468108
-
项目类别:
-
资助金额:$3.19万
-
财政年份:1991
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
Characterization of the S. Pombe cAMP Pathway
-
批准号:6636033
-
项目类别:
-
资助金额:$30.6万
-
财政年份:1991
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
S POMBE CAMP SIGNAL PATHWAY
-
批准号:2183729
-
项目类别:
-
资助金额:$11.74万
-
财政年份:1991
-
负责人:CHARLES S. HOFFMAN
-
依托单位:
海外基金