Role of the Parkinson's susceptibility gene LRRK2 in NFAT-mediated malignant mesothelioma tumorigenesis
帕金森病易感基因 LRRK2 在 NFAT 介导的恶性间皮瘤肿瘤发生中的作用
基本信息
- 批准号:10653572
- 负责人:
- 金额:$ 9.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAmphibolesAsbestosAsbestos-Related Malignant MesotheliomaBindingBiologicalBiological MarkersBiological ModelsCSNK1A1 geneCalmodulinCell LineCell NucleusCellsClinicalComplexCytosolDNADevelopmentDiseaseDisease ManagementDissociationEnvironmentExposure toFamilyFamily Cancer HistoryFiberFutureGenesGenetic TranscriptionGerm-Line MutationGoalsHeterozygoteHumanImmune responseIndividualInflammationInflammatoryInterphase CellLRRK2 geneLinkMalignant NeoplasmsMalignant Pleural MesotheliomaMalignant mesotheliomaMalignant neoplasm of lungMediatingMesotheliomaMolecular BiologyMolecular ConformationMusMutationNormal CellNuclear TranslocationOperative Surgical ProceduresOutcomeParkinson DiseasePathogenesisPathway interactionsPatientsPericardial cavityPeritonealPhosphorylationPhosphotransferasesPlayPleuralPrecision therapeuticsPredispositionProcessProtein DephosphorylationPublic HealthReactive Oxygen SpeciesRefractory DiseaseReportingResistanceRestRiskRoleSiblingsSignal PathwaySignal TransductionSomatic MutationSpecimenStimulusSusceptibility GeneTestingTherapeuticThickThinnessTissuesTumor Suppressor GenesTumor Suppressor ProteinsVariantWild Type Mousebody cavitycalcineurin phosphatasecancer cellcarcinogenesiscarcinogenicitycell transformationcheckpoint therapydisorder preventiongene productgenome sequencingimprovedin vivomalignant breast neoplasmmouse modelnovelnovel strategiesnuclear factors of activated T-cellspatient stratificationprotein expressionresponsetumortumor-immune system interactionstumorigenesiswhole genome
项目摘要
PROJECT SUMMARY/ABSTRACT
Malignant Mesothelioma (MM), particularly the pleural form of this disease, is a treatment-resistant, rapidly fatal
cancer of serosal cells lining the internal body cavities. Exposure to asbestos is causally associated with the
development of MM, and asbestos-induced inflammation is a major contributing factor in this process. In some
families, heterozygous germline mutations in certain cancer-related genes, especially BAP1, predispose to MM,
and mouse models carrying Bap1 mutations have enhanced susceptibility to the carcinogenic effects of
asbestos. Moreover, somatic BAP1 mutations/deletions occur in 50-60% of human MM specimens. Our recent
whole genome sequencing study of MM patients with a family history of cancer uncovered two families with
germline mutations in the Parkinson’s susceptibility gene LRRK2, including a truncating mutation in one family
in which 6 siblings developed pleural MM. We later found loss of LRRK2 protein expression in 61% of primary
pleural MPMs and MPM cell lines from unrelated individuals. LRRK2 has been linked with various cellular
pathways, one of which (NFAT signaling) is implicated in inflammation/immune response and carcinogenesis.
Our broad, long-term objective is to determine if LRRK2 loss contributes to MM formation and progression, in
part, by dysregulating NFAT, and whether targeting this pathway would have significant therapeutic benefits. In
this project, we propose to test whether LRRK2-mediated interactions with NFAT play a key role in asbestos-
induced inflammation and MM tumorigenesis. Our hypothesis is that LRRK2 acts as a tumor suppressor gene
in MM, that loss of LRRK2 expression contributes significantly to MM pathogenesis, and that future therapeutic
approaches exploiting functional attributes associated with LRRK2 loss can lead to improved clinical outcomes
in this disease. Overall, this project seeks to elucidate mechanisms by which inactivation of LRRK2 contributes
to asbestos carcinogenesis and MM development using a combination of cell biological and in vivo approaches.
We propose the following Specific Aims: 1) Does LRRK2 loss promote asbestos-induced tumorigenesis? We
will determine if Lrrk2-deficient mice are predisposed to the carcinogenic effects of asbestos, as demonstrated
by accelerated asbestos-induced MM development compared to wild-type (WT) littermates. Additionally, we will
ascertain if the immune tumor microenvironment differs between MMs from Lrrk2-deficient mice and MMs from
WT mice, and if a comparable difference occurs in human MPM. 2) Does LRRK2 loss enhance NFAT-driven
inflammatory signaling? Asbestos is thought to contribute to MPM development by inducing inflammation, and
we propose to test whether LRRK2 suppresses such inflammation by dampening activity of the transcription
factor NFAT. LRRK2 has been shown to bind to the NRON complex, blocking transport of NFAT from the cytosol
to the nucleus when cells are in a resting state. Loss of LRRK2 will therefore be expected to cause NFAT to be
translocated to the nucleus to mediate transcription. Here we will test if this mechanism may explain how LRRK2
loss may potentiate asbestos-induced inflammation and MM tumorigenesis.
项目概要/摘要
恶性间皮瘤 (MM),尤其是这种疾病的胸膜形式,是一种难治性、快速致命的疾病
体内腔内浆膜细胞的癌症与接触石棉有因果关系。
MM 的发展,而石棉引起的炎症是这一过程中的一个主要因素。
某些癌症相关基因(尤其是 BAP1)的杂合种系突变易患 MM,
携带 Bap1 突变的小鼠模型对致癌作用的敏感性增强
此外,我们最近的 50-60% 人类 MM 样本中出现体细胞 BAP1 突变/缺失。
对有癌症家族史的多发性骨髓瘤患者的全基因组测序研究发现,两个家族患有癌症
帕金森氏症易感基因 LRRK2 的种系突变,包括一个家族的截短突变
其中 6 名兄弟姐妹患有胸膜 MM,后来我们发现 61% 的原发性骨髓瘤中 LRRK2 蛋白表达缺失。
来自不相关个体的胸膜 MPM 和 MPM 细胞系已与多种细胞相关。
途径,其中之一(NFAT 信号传导)与炎症/免疫反应和致癌作用有关。
我们广泛的长期目标是确定 LRRK2 缺失是否会导致 MM 的形成和进展,
部分原因是 NFAT 失调,以及针对该通路是否会产生显着的治疗益处。
在这个项目中,我们建议测试 LRRK2 介导的与 NFAT 的相互作用是否在石棉-
我们的假设是 LRRK2 充当肿瘤抑制基因。
在 MM 中,LRRK2 表达的丧失对 MM 发病机制有显着影响,未来的治疗
利用与 LRRK2 丢失相关的功能属性的方法可以改善临床结果
总体而言,该项目旨在阐明 LRRK2 失活的机制。
结合细胞生物学和体内方法研究石棉致癌和多发性骨髓瘤的发展。
我们提出以下具体目标:1)LRRK2 缺失是否会促进石棉诱导的肿瘤发生?
将确定 Lrrk2 缺陷小鼠是否容易受到石棉的致癌作用,如所证明的
与野生型 (WT) 同窝小鼠相比,石棉诱导的 MM 发育加速。
确定 Lrrk2 缺陷小鼠的 MM 和来自 Lrrk2 缺陷小鼠的 MM 之间的免疫肿瘤微环境是否不同
WT 小鼠,以及如果人类 MPM 中出现类似差异 2) LRRK2 丢失是否会增强 NFAT 驱动。
石棉被认为通过诱导炎症促进 MPM 的发展,以及
我们建议测试 LRRK2 是否通过抑制转录活性来抑制这种炎症
NFAT 因子已被证明可以与 NRON 复合物结合,阻断 NFAT 从细胞质中的转运。
因此,当细胞处于静息状态时,LRRK2 的缺失将导致 NFAT 发生变化。
在这里,我们将测试这种机制是否可以解释 LRRK2 的机制。
损失可能会加剧石棉诱发的炎症和多发性骨髓瘤(MM)肿瘤的发生。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Joseph R. Testa其他文献
Unusual karyotypic changes and B cell involvement in a case of lymph node blast crisis of chronic myelogenous leukemia.
慢性粒细胞白血病淋巴结母细胞危象一例异常核型变化和 B 细胞受累。
- DOI:
- 发表时间:
1984 - 期刊:
- 影响因子:20.3
- 作者:
DE Hogge;Shinichi Misawa;Joseph R. Testa;Richard D. Leavitt;A. Pollak;Charles A. Schiffer - 通讯作者:
Charles A. Schiffer
Amplification of the c-myc oncogene is associated with an abnormally banded region on chromosome 8 or double minute chromosomes in two HL-60 human leukemia sublines.
c-myc 癌基因的扩增与两个 HL-60 人类白血病亚系中 8 号染色体或双小染色体上的异常带状区域有关。
- DOI:
- 发表时间:
1987 - 期刊:
- 影响因子:0
- 作者:
Shinichi Misawa;Stephen P. Staal;Joseph R. Testa - 通讯作者:
Joseph R. Testa
Double Minute Chromosomes in Acute Myeloblastic Leukemia 1,2
急性髓细胞白血病 1,2 中的双分钟染色体
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
N. Oguma;Nanao Kamada;Atsushi Kuramoto;Kimio Tanaka;Shinichi Misawa;Joseph R. Testa - 通讯作者:
Joseph R. Testa
A genetic, physical, and comparative map of rat chromosome 10
大鼠 10 号染色体的遗传、物理和比较图
- DOI:
10.1007/s003359900126 - 发表时间:
2009 - 期刊:
- 影响因子:2.5
- 作者:
Raymond S. Yeung;Kenneth H. Buetow;T. Scherpbier;Daphne W. Bell;Joseph R. Testa - 通讯作者:
Joseph R. Testa
Novel human and mouse annexin A10 are linked to the genome duplications during early chordate evolution.
新型人类和小鼠膜联蛋白 A10 与早期脊索动物进化过程中的基因组复制有关。
- DOI:
- 发表时间:
1999 - 期刊:
- 影响因子:4.4
- 作者:
R. O. Morgan;N. Jenkins;D. Gilbert;N. Copeland;B. Balsara;Joseph R. Testa;M. Fernández - 通讯作者:
M. Fernández
Joseph R. Testa的其他文献
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{{ truncateString('Joseph R. Testa', 18)}}的其他基金
AKT AND TUMOR SUPPRESSOR PATHWAYS IN MESOTHELIOMA
间皮瘤中的 AKT 和肿瘤抑制途径
- 批准号:
7035624 - 财政年份:2005
- 资助金额:
$ 9.4万 - 项目类别:
AKT as a Biomarker of Ovarian Cancer Progression and a Target for Therapeutic Int
AKT 作为卵巢癌进展的生物标志物和治疗整合的靶点
- 批准号:
6958701 - 财政年份:2004
- 资助金额:
$ 9.4万 - 项目类别:
Role of PI3 kinase/AKT2 signaling in ovarian oncogenesis
PI3激酶/AKT2信号在卵巢肿瘤发生中的作用
- 批准号:
6667423 - 财政年份:2002
- 资助金额:
$ 9.4万 - 项目类别:
Role of PI3 kinase/AKT2 signaling in ovarian oncogenesis
PI3激酶/AKT2信号在卵巢肿瘤发生中的作用
- 批准号:
6504970 - 财政年份:2001
- 资助金额:
$ 9.4万 - 项目类别:
Role of PI3 kinase/AKT2 signaling in ovarian oncogenesis
PI3激酶/AKT2信号在卵巢肿瘤发生中的作用
- 批准号:
6352800 - 财政年份:2000
- 资助金额:
$ 9.4万 - 项目类别:
Role of PI3 kinase/AKT2 signaling in ovarian oncogenesis
PI3激酶/AKT2信号在卵巢肿瘤发生中的作用
- 批准号:
6323313 - 财政年份:1999
- 资助金额:
$ 9.4万 - 项目类别:
Role of PI3 kinase/AKT2 signaling in ovarian oncogenesis
PI3激酶/AKT2信号在卵巢肿瘤发生中的作用
- 批准号:
6230163 - 财政年份:1999
- 资助金额:
$ 9.4万 - 项目类别:
Basis for Lymphomagenesis in Akt2 Transgenic Mice
Akt2 转基因小鼠淋巴瘤发生的基础
- 批准号:
7989134 - 财政年份:1998
- 资助金额:
$ 9.4万 - 项目类别:
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