Histone modifications regulating phenotype plasticity: Role of non-canonical Wnt signaling
Histone modifications regulating phenotype plasticity: Role of non-canonical Wnt signaling
批准号:
10011776
负责人:
Marie Ruth Webster
金额:
$24.65万
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:
2019-09-05 至 2022-08-31
关键词:
3-DimensionalAddressAffectAutomobile DrivingBiological AssayCell CycleCell LineCell MaintenanceCell ProliferationCellsCharacteristicsChromatinClinicalDataDevelopmentDrug resistanceDyesEpigenetic ProcessExhibitsGene ExpressionGene SilencingGenerationsGeneticGoalsGrowthHistone H3HumanHuman ResourcesHypermethylationIn VitroInvadedKDM5B geneKnowledgeLysineMaintenanceMalignant NeoplasmsMalignant neoplasm of prostateMelanoma CellMembraneMentorsMetastatic MelanomaMethylationMethyltransferaseMolecularNeoplasm MetastasisNude MicePathway interactionsPatientsPennsylvaniaPhenotypePlasmidsPopulationPublishingRegulationRelapseReporterResearchResearch PersonnelResistanceResourcesRoleSETDB1 geneSignal TransductionSkinSkin CancerSnailsStressSubcutaneous InjectionsThe Wistar InstituteTherapeuticTrainingTraining SupportTumor Stem CellsTumor Suppressor GenesTumor Suppressor ProteinsTumorigenicityUniversitiesWNT Signaling Pathwayaggressive therapybasebiological adaptation to stresscancer stem cellcancer typecareercareer developmentcell motilitychemotherapydesignhistone methylationhistone methyltransferasehistone modificationin vivoin vivo imaging systeminhibitor/antagonistinsightknock-downmalignant breast neoplasmmelanocytemelanomaneoplastic cellnovel therapeutic interventionpre-doctoralresponseself-renewalsenescenceskillssmall moleculestemstem-like cellsubcutaneoussuccesstargeted treatmenttherapy resistanttumortumor growthtumor progression
中文摘要
项目总结:
这条通往独立、职业和发展之路的提案的主要目标是请求和支持他们。
培训将帮助他们发展癌症和表观遗传学方面的专业知识,同时解决细胞周期缓慢和细胞周期延长的关键作用。
组蛋白修饰在高度耐药的转移性黑色素瘤的表型和可塑性方面起作用。
在此期间,作为一名独立的癌症患者,我的职业生涯的一部分将成为我成功的癌症发展计划不可或缺的一部分。
研究人员。他在本提案中概述的全球培训计划将充分利用中国目前广泛的培训资源。
威斯塔学院、宾夕法尼亚州立大学以及坦普尔大学。我的职业培训计划也将受到他们的指导。
曾成功指导过博士后、临床医学研究员等高级临床医学人员。
学术和事业都是如此。
这项提议的主要科学部分侧重于从实验上确定新的分子生物学机制。
侵袭性黑色素瘤的潜在表型、可塑性和治疗耐药基因,以及表观遗传学的主要作用。
慢循环细胞的表型、可塑性和维持性的变化。这些拟议的研究都是基于生物多样性的。
我之前的研究发现,黑色素瘤细胞的一个亚群可以表达Wnt5A基因和p21基因,可以在多种类型的细胞中存活。
他们的压力来自于进入一个缓慢循环的、类似于衰老的国家,但他们仍然会入侵中国,并保持他们形成的能力。
转移。我的初步研究数据表明,SEDTB1基因的表达与肺癌的一种侵袭性表型相关。
人类非侵袭性黑色素瘤细胞株和非侵袭性非侵袭性黑色素瘤细胞株继续形成更具侵袭性的表型。
Wnt5A的表达增加了SETDB1的表达,而SETDB1的表达则是组蛋白。
甲基转移酶也被认为与肿瘤抑制基因p16的沉默有关。p16基因在细胞中也有表达。
黑素细胞参与了黑色素瘤的早期进展,但在黑色素瘤进展过程中它并未丢失,这与此相关。
随着p21基因的表达,并在应激后出现类似衰老的免疫反应。它发生在黑色素瘤中,并伴随着甲基化。
目前还没有观察到肿瘤的进展情况,这可能会阻止多种肿瘤抑制因子基因的表达,但不会影响肿瘤的发展。
具体的表观遗传学变化在表型、可塑性和耐药性中的作用在很大程度上仍是未知的。
因此,根据这些数据,我将继续探讨以下科学研究目标:(1)进一步阐明其运行机制。
到那时,Wnt5A和;将促进干细胞样细胞缓慢循环的日常维护;Wnt5A和P21将继续确定是否需要。
组蛋白修饰是由SETDB1诱导的,可促进黑色素瘤细胞的表型可塑性和侵袭性。
这项建议中提出的各项科学研究目标的最终完成,将有助于我在这方面的研究、技能和知识水平的发展。
癌症与表观遗传学的关系,同时还勾勒出了一种新的机制,即高度侵袭性的、具有抗性的细胞可以逃避压力。
促进黑色素瘤转移,治疗耐药。
英文摘要
Project Summary
The goals of this Pathway to Independence Career Development proposal are to request support for
training to develop expertise in cancer epigenetics while addressing the role of slow cycling cells and
histone modifications in phenotype plasticity of highly resistant metastatic melanoma. K99/R00 support
during this part of my career will be integral to my successful development as an independent cancer
researcher. The training plan outlined in this proposal will take advantage of the extensive resources at The
Wistar Institute, University of Pennsylvania as well as Temple University. My training will also be guided by
senior personnel who have successfully mentored predoctoral, postdoctoral, and clinical fellows in
academic careers.
The scientific portion of this proposal focuses on experimentally determining the molecular mechanism
underlying phenotype plasticity and therapy resistance of invasive melanoma and the role of epigenetic
changes in phenotype plasticity and maintenance of slow cycling cells. The proposed studies are based on
my previous findings that a subset of melanoma cells, which express Wnt5A and p21, survive multiple types
of stress by entering a slow-cycling, senescent-like state, but still invade and retain the ability to form
metastases. My preliminary data suggest SEDTB1 expression correlates with an invasive phenotype in our
human melanoma cell lines and driving non-invasive melanoma cells to a more invasive phenotype, through
over expression of Wnt5A, increases SETDB1 expression. Expression of SETDB1, a histone
methyltransferase, has been implicated in the silencing of tumor suppressor p16. p16 is expressed in
melanocytes and early stages of melanoma but is lost during melanoma progression and this correlates
with p21 expression and a senescent-like response following stress. In melanoma, hypermethylation during
tumor progression is observed, which may block the expression of multiple tumor suppressor genes, but the
role of specific epigenetic changes in phenotype plasticity and drug resistance is still largely unknown.
Therefore, in line with these data I will explore the following scientific aims: 1) to elucidate the mechanism
by which Wnt5A and p21 promote the maintenance of slow cycling stem-like cells;; and 2) to determine if
histone modifications induced by SETDB1 promote phenotype plasticity and invasion in melanoma cells.
The completion of the scientific aims in this proposal will develop my research skills and knowledge in
cancer epigenetics while delineating the mechanism by which highly invasive resistant cells evade stress to
promote melanoma metastasis and therapy resistance.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Histone modifications regulating phenotype plasticity: Role of non-canonical Wnt signaling
-
批准号:10248309
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2019
-
负责人:Marie Ruth Webster
-
依托单位:
海外基金