Opioid Peptide Synthesizing Enzymes
Opioid Peptide Synthesizing Enzymes
批准号:
10163827
负责人:
IRIS LINDBERG
金额:
$34.5万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-07-15 至 2023-05-31
关键词:
AddressAffectBindingBinding ProteinsBiochemicalBiologicalBody WeightC-terminalCell Culture TechniquesCell modelCellsCellular biologyChildClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsCorticotropinDefectDesire for foodDevelopmentDiabetes MellitusDiseaseDistressDominant-Negative MutationDrug AddictionDrug abuseEatingEndocrineEnergy MetabolismEngineeringEnvironmentEnzymesExhibitsGenesGenetic PolymorphismGenotypeHalf-LifeHeterozygoteHigh Fat DietHomeostasisHomozygoteHumanHuman BiologyHypothalamic structureImpairmentInterruptionInvestigationKnockout MiceLaboratoriesLearningLoxP-flanked alleleMediatingModelingMolecular ChaperonesMolecular ConformationMusMutant Strains MiceMutationNeuronsNeuropeptidesObesityOpioidOpioid PeptidePathway interactionsPeptide HydrolasesPeptide Signal SequencesPeptidesPhenotypePhysiologicalPlayPredispositionPro-OpiomelanocortinProcessProductionProhormone ConvertasePropertyProprotein Convertase 1Proprotein Convertase 2Protein PrecursorsProteinsRewardsRisk FactorsRoleSatiationSignal TransductionStressTestingTissuesVariantWild Type MouseWorkalpha-Melanocyte stimulating hormoneanorexicbasebeta-Endorphincostendoplasmic reticulum stressenergy balanceenzyme pathwayfeedingglucose metabolismhormonal signalsin vivoinhibitor/antagonistinsightlipid metabolismmouse modelmutantneuronal circuitrynovelobesity riskpain signalpediatric patientspeptide Arelating to nervous systemstressortrafficking
中文摘要
激素原转化酶PC1/3和PC2分别由PCSK1和PCSK2基因编码
英文摘要
The prohormone convertases PC1/3 and PC2, encoded by the genes PCSK1 and PCSK2 respectively, are the
endoproteolytic enzymes responsible for the liberation of opioid-active peptides from larger precursor
proteins. Prohormone convertases play important roles not only in opioid peptide-mediated pain signaling
but also function in many other neuronal circuits, including in reward pathways and in hypothalamic
circuits involved in feeding and energy homeostasis. For example, both rare and common variations in
PCSK1 function as major risk factors for human obesity, potentially due to deficiencies in hypothalamic
peptidergic processing. In collaboration with clinicians who have identified children with novel mutations
in PCSK1, we have recently determined that mutant human and mouse PC1/3 proteins are subject to
targeting defects which are likely to result in hypothalamic proteostatic stress. Based on our prior finding
that mouse PC1/3 proteins oligomerize during synthesis, we propose that dominant-negative interactions
play a major role in human PC1/3 heterozygote obesity phenotypes, affecting precursor processing to
bioactive peptides involved in satiety signaling. We propose that external stressors will exacerbate even
mild forms of PC1/3 conformational distress, impairing C-terminal cleavage of PC1/3 to the smaller, more
active forms. These processes will ultimately converge to strongly impair precursor processing, eg.
proopiomelanocortin cleavage to beta-endorphin, ACTH, and most importantly, to the anorexic peptide α-
MSH. In the present proposal we will use CRISPR-engineered cell models to elucidate the cell biology and
precursor processing efficacy of three human PC1/3 variants and mutants known to be strongly associated
with increased risk of obesity. Secondly, we will create mouse models of two common human PCSK1
obesity mutants, and a third model of a rare but highly impaired mutant, to extend findings made in cell
culture to actual secretory tissues, and to identify the specific physiologic alterations which underlie the
PCSK1-mediated obesity phenotype. Lastly, we will test our hypothesis that processing deficits in
proopiomelanocortin-synthesizing neurons underlie the obesity phenotype by selectively eliminating Pcsk1
expression in proopiomelanocortin-expressing cells using a floxed Pcsk1 null mouse model. The results of
these studies will illuminate the biosynthetic mechanisms controlling hypothalamic peptide production
that contribute to human susceptibility to a variety of diseases, from obesity to reward pathways in drug
addiction.
期刊论文(4)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1210/endocr/bqab155
发表时间:
2021-12-01
期刊:
Endocrinology
影响因子:
4.8
作者:
[Lindberg I, Fricker LD]
通讯作者:
Fricker LD
ProSAAS-mediated neuroprotective mechanisms in Alzheimer's and Parkinson's diseases: the role of secretory chaperones in neurodegeneration
-
批准号:10327703
-
项目类别:
-
资助金额:$63.37万
-
财政年份:2019
-
负责人:IRIS LINDBERG
-
依托单位:
ProSAAS-mediated neuroprotective mechanisms in Alzheimer's and Parkinson's diseases: the role of secretory chaperones in neurodegeneration
-
批准号:10532769
-
项目类别:
-
资助金额:$63.37万
-
财政年份:2019
-
负责人:IRIS LINDBERG
-
依托单位:
ProSAAS-mediated neuroprotective mechanisms in Alzheimer's and Parkinson's diseases: the role of secretory chaperones in neurodegeneration
-
批准号:10062465
-
项目类别:
-
资助金额:$63.37万
-
财政年份:2019
-
负责人:IRIS LINDBERG
-
依托单位:
The Secretory Chaperone 7B2 as an Endogenous Regulator of Amyloid Pathology
-
批准号:8919199
-
项目类别:
-
资助金额:$22.75万
-
财政年份:2014
-
负责人:IRIS LINDBERG
-
依托单位:
The Secretory Chaperone 7B2 as an Endogenous Regulator of Amyloid Pathology
-
批准号:8568474
-
项目类别:
-
资助金额:$19.96万
-
财政年份:2014
-
负责人:IRIS LINDBERG
-
依托单位:
Identification of Novel Peptide Hormones
-
批准号:7708007
-
项目类别:
-
资助金额:$22.5万
-
财政年份:2009
-
负责人:IRIS LINDBERG
-
依托单位:
Deorphanizing the Peptidome
-
批准号:8094525
-
项目类别:
-
资助金额:$28.67万
-
财政年份:2009
-
负责人:IRIS LINDBERG
-
依托单位:
Deorphanizing the Peptidome
-
批准号:8274836
-
项目类别:
-
资助金额:$28.67万
-
财政年份:2009
-
负责人:IRIS LINDBERG
-
依托单位:
Deorphanizing the Peptidome
-
批准号:7726444
-
项目类别:
-
资助金额:$31.15万
-
财政年份:2009
-
负责人:IRIS LINDBERG
-
依托单位:
Deorphanizing the Peptidome
-
批准号:7895710
-
项目类别:
-
资助金额:$29.55万
-
财政年份:2009
-
负责人:IRIS LINDBERG
-
依托单位:
Identification of Novel Peptide Hormones
-
批准号:7849751
-
项目类别:
-
资助金额:$18.75万
-
财政年份:2009
-
负责人:IRIS LINDBERG
-
依托单位:
Control of peptide hormone biosynthesis by PC2 and 7B2
-
批准号:7991571
-
项目类别:
-
资助金额:$7.0万
-
财政年份:2009
-
负责人:IRIS LINDBERG
-
依托单位:
Blockade of Anthrax Cytotoxicity Using Furin Inhibitors
-
批准号:6665136
-
项目类别:
-
资助金额:$17.75万
-
财政年份:2002
-
负责人:IRIS LINDBERG
-
依托单位:
Proprotein Processing, Trafficking and Secretion Gordon Conference
-
批准号:6895472
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2002
-
负责人:IRIS LINDBERG
-
依托单位:
Blockade of Anthrax Cytotoxicity Using Furin Inhibitors
-
批准号:6562575
-
项目类别:
-
资助金额:$20.46万
-
财政年份:2002
-
负责人:IRIS LINDBERG
-
依托单位:
Hormonal and Neural Peptide Biosynthesis (Gordon Confer)
-
批准号:6747940
-
项目类别:
-
资助金额:$1.5万
-
财政年份:2002
-
负责人:IRIS LINDBERG
-
依托单位:
CONTROL OF PEPTIDE HORMONE BIOSYNTHESIS BY PC2 AND 7B2
-
批准号:6094813
-
项目类别:
-
资助金额:$2.79万
-
财政年份:1999
-
负责人:IRIS LINDBERG
-
依托单位:
CONTROL OF PEPTIDE HORMONE BIOSYNTHESIS BY PC2 AND 7B2
-
批准号:2859206
-
项目类别:
-
资助金额:$2.71万
-
财政年份:1998
-
负责人:IRIS LINDBERG
-
依托单位:
CONTROL OF PEPTIDE HORMONE BIOSYNTHESIS BY PC2 AND 7B2
-
批准号:6203939
-
项目类别:
-
资助金额:$6.58万
-
财政年份:1996
-
负责人:IRIS LINDBERG
-
依托单位:
Control of peptide hormone biosynthesis by PC2 and 7B2
-
批准号:8050538
-
项目类别:
-
资助金额:$33.62万
-
财政年份:1996
-
负责人:IRIS LINDBERG
-
依托单位:
海外基金