Growth hormone actions in prostate carcinogenesis
Growth hormone actions in prostate carcinogenesis
批准号:
10063500
负责人:
Paul C Marker
金额:
$20.7万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-12-01 至 2021-11-30
关键词:
AcromegalyAddressAllelesBirthBlood CirculationCancer PatientClinicalClinical ResearchControl GroupsDevelopmentDiabetes MellitusDiseaseEpithelialFDA approvedFutureGenesGeneticGenetic RecombinationGrowth Hormone ReceptorGrowth InhibitorsHumanInsulin-Like Growth Factor IKnowledgeLaron SyndromeLeadLiverLoxP-flanked alleleMalignant NeoplasmsMalignant neoplasm of prostateMediatingModelingMusPI3K/AKTPathway interactionsPatientsPharmaceutical PreparationsPlayProstateProstatic NeoplasmsPublishingRB1 geneRattusReceptor ActivationReceptor SignalingRiskRodentRoleSignal TransductionSomatotropinStat5 proteinTP53 geneTamoxifenTestingTherapeuticTimeTissuesTransgenesTumor Suppressor ProteinsUp-Regulationage relatedagedcohortexperimental groupexperimental studygenetic approachinnovationmalemeetingsmouse modelmutantnull mutationpegvisomantprobasinprostate cancer cellprostate cancer modelprostate cancer preventionprostate cancer progressionprostate carcinogenesispublic health relevancetargeted agenttargeted treatmenttumortumor progressiontumorigenic
中文摘要
摘要
生长激素/胰岛素样生长因子-1(GH/IGF-1)轴与年龄相关疾病有关
包括前列腺癌患有Laron综合征的人缺乏功能性生长激素受体(GHR),
降低了癌症和糖尿病的发病率。具有Ghr纯合无效突变的小鼠也受到保护,
C3(1)/TAg前列腺癌模型中的癌症。同样,缺乏功能性生长激素基因的大鼠
前列腺癌在Probasin/TAg模型中。GHR在多种组织中表达,包括肝脏和
前列腺GH激活肝脏中的GHR是刺激IGF-1释放到肝脏中的主要机制。
流通许多GH作用是由IGF-1在靶组织中的后续作用介导的,包括
前列腺此外,来自人类的证据表明,循环IGF-1升高会增加
包括前列腺癌在内的几种癌症的发展。生长激素受体在正常前列腺组织中的表达
这表明GHR的局部信号传导在前列腺癌中也很重要
细胞最近的研究表明,前列腺癌细胞局部生长激素合成的上调是前列腺癌的一个重要因素。
癌症进展的共同特征进一步支持了局部GH/GHR作用的潜在重要性,
前列腺癌然而,GH/IGF-1轴在前列腺癌中的作用的几个重要方面仍然存在
不确定现有的研究尚未解决在不同的生长激素水平下对GH信号传导的潜在持续需求。
前列腺癌进展的阶段,前列腺癌细胞中局部GHR信号传导的作用,或前列腺癌细胞中局部GHR信号传导的作用。
GHR激活下游的转导机制在前列腺癌中很重要。This project will use
创新的遗传方法在小鼠中,以解决目前知识的这些局限性。既往啮齿动物研究
也是有限的,因为他们只关注由TP 53和RB 1功能破坏驱动的肿瘤。
肿瘤抑制剂。该项目将进一步确定完整GHR信号的要求是否扩展到
前列腺癌的小鼠模型由PI 3 K/AKT通路的激活驱动,
在人类前列腺癌中。完成这些研究将是确定最佳方案的重要一步。
使用靶向GH/IGF-1轴的pegvisomant或其他药剂治疗和/或预防
前列腺癌
英文摘要
Abstract
The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis has been implicated in age related diseases
including prostate cancer. Humans with Laron syndrome lack functional growth hormone receptors (GHRs) and
have reduced rates of cancer and diabetes. Mice with homozygous null mutations in Ghr are also protected from
cancer in the C3(1)/TAg prostate cancer model. Similarly, rats lacking a functional GH gene are protected
prostate cancers in the Probasin/TAg model. GHRs are expressed in multiple tissues including the liver and
prostate. Activation of GHRs in the liver by GH is the main mechanism that stimulates the release of IGF-1 into
circulation. Many GH actions are mediated by the subsequent actions of IGF-1 in target tissues including the
prostate. Furthermore, evidence from humans indicates that elevated circulating IGF-1 confers an increased risk
for the development of several cancers including prostate cancer. The expression of GHRs in the normal prostate
and by prostate cancer cells suggests that local signaling by GHRs may also be important in prostate cancer
cells. Recent studies demonstrating that up-regulation of local GH synthesis by prostate cancer cells is a
common feature of cancer progression further supports the potential importance of local GH/GHR actions in
prostate cancer. However, several important aspects of the role of GH/IGF-1 axis in prostate cancer remain
uncertain. Available studies have not addressed the potential ongoing requirement for GH signaling at different
stages of prostate cancer progression, the role of local GHR signaling in prostate cancer cells, or the signal
transduction mechanisms downstream of GHR activation important in prostate cancer. This project will use
innovative genetic approaches in mice to address these limitations of current knowledge. Previous rodent studies
were also limited because they focused only on tumors driven by disruption the function of the TP53 and RB1
tumor suppressors. This project will further determine if the requirement for intact GHR signaling extends to
mouse models for prostate cancers driven by activation of the PI3K/AKT pathway that is also commonly observed
in human prostate cancers. Completion of these studies will be an important step toward identifying the best
ways to employ pegvisomant or other agents targeting the GH/IGF-1 axis for the treatment and/or prevention of
prostate cancer.
期刊论文(5)
专著(0)
科研奖励(0)
会议论文
Conditional gene regulation models demonstrate a pro-proliferative role for growth hormone receptor in prostate cancer.
条件基因调控模型证明生长激素受体在前列腺癌中具有促增殖作用。
DOI:
10.1002/pros.24474
发表时间:
2023
期刊:
The Prostate
影响因子:
--
作者:
[Unterberger,ChristopherJ, McIlwain,SeanJ, Tsourkas,PhilipposK, Maklakova,VilenaI, Prince,JordynL, Onesti,Abigail, Hu,Rong, Kopchick,JohnJ, Swanson,StevenM, Marker,PaulC]
通讯作者:
Marker,PaulC
Mammary Tumor Growth and Proliferation Are Dependent on Growth Hormone in Female SV40 C3(1) T-Antigen Mice.
雌性 SV40 C3(1) T 抗原小鼠的乳腺肿瘤生长和增殖依赖于生长激素。
DOI:
10.1210/endocr/bqac174
发表时间:
2022
期刊:
Endocrinology
影响因子:
4.8
作者:
[Unterberger,ChristopherJ, McGregor,StephanieM, Kopchick,JohnJ, Swanson,StevenM, Marker,PaulC]
通讯作者:
Marker,PaulC
Magi2 in aggressive prostate cancer
-
批准号:9024983
-
项目类别:
-
资助金额:$16.18万
-
财政年份:2015
-
负责人:Paul C Marker
-
依托单位:
Magi2 in aggressive prostate cancer
-
批准号:9187439
-
项目类别:
-
资助金额:$19.51万
-
财政年份:2015
-
负责人:Paul C Marker
-
依托单位:
Steroid hormones and SFRP1 in the age-related incidence of BPH and BOO
-
批准号:8328840
-
项目类别:
-
资助金额:$32.22万
-
财政年份:2011
-
负责人:Paul C Marker
-
依托单位:
Steroid hormones and SFRP1 in the age-related incidence of BPH and BOO
-
批准号:8715776
-
项目类别:
-
资助金额:$32.22万
-
财政年份:2011
-
负责人:Paul C Marker
-
依托单位:
Steroid hormones and SFRP1 in the age-related incidence of BPH and BOO
-
批准号:8528576
-
项目类别:
-
资助金额:$31.1万
-
财政年份:2011
-
负责人:Paul C Marker
-
依托单位:
Steroid hormones and SFRP1 in the age-related incidence of BPH and BOO
-
批准号:8186950
-
项目类别:
-
资助金额:$37.13万
-
财政年份:2011
-
负责人:Paul C Marker
-
依托单位:
Novel prostate cancer oncogenes identified by transposon mutagenesis
-
批准号:8034799
-
项目类别:
-
资助金额:$29.16万
-
财政年份:2010
-
负责人:Paul C Marker
-
依托单位:
Novel prostate cancer oncogenes identified by transposon mutagenesis
-
批准号:8403838
-
项目类别:
-
资助金额:$27.77万
-
财政年份:2010
-
负责人:Paul C Marker
-
依托单位:
Novel prostate cancer oncogenes identified by transposon mutagenesis
-
批准号:7889176
-
项目类别:
-
资助金额:$29.79万
-
财政年份:2010
-
负责人:Paul C Marker
-
依托单位:
Novel prostate cancer oncogenes identified by transposon mutagenesis
-
批准号:8204600
-
项目类别:
-
资助金额:$29.43万
-
财政年份:2010
-
负责人:Paul C Marker
-
依托单位:
Genetic Analysis of a Prostate Tumor Suppressor Region
-
批准号:7614446
-
项目类别:
-
资助金额:$28.97万
-
财政年份:2006
-
负责人:Paul C Marker
-
依托单位:
Genetic Analysis of a Prostate Tumor Suppressor Region
-
批准号:7794849
-
项目类别:
-
资助金额:$28.68万
-
财政年份:2006
-
负责人:Paul C Marker
-
依托单位:
Genetic Analysis of a Prostate Tumor Suppressor Region
-
批准号:7365080
-
项目类别:
-
资助金额:$28.97万
-
财政年份:2006
-
负责人:Paul C Marker
-
依托单位:
Genetic Analysis of a Prostate Tumor Suppressor Region
-
批准号:7189080
-
项目类别:
-
资助金额:$29.76万
-
财政年份:2006
-
负责人:Paul C Marker
-
依托单位:
Genetic Analysis of a Prostate Tumor Suppressor Region
-
批准号:7031405
-
项目类别:
-
资助金额:$29.87万
-
财政年份:2006
-
负责人:Paul C Marker
-
依托单位:
Identification of prostate-specific regulation elements
-
批准号:6952465
-
项目类别:
-
资助金额:$14.85万
-
财政年份:2004
-
负责人:Paul C Marker
-
依托单位:
Identification of prostate-specific regulation elements
-
批准号:6850406
-
项目类别:
-
资助金额:$14.85万
-
财政年份:2004
-
负责人:Paul C Marker
-
依托单位:
海外基金