Project 2: Understanding the Cellular Origins of Melanoma
项目 2:了解黑色素瘤的细胞起源
基本信息
- 批准号:10392898
- 负责人:
- 金额:$ 42.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAffectAllelesBRAF geneBehaviorBenignCellsClinicalCommunitiesDataDevelopmentDiffuseDiseaseEnvironmentEventExcisionFailureFeedbackFrequenciesGrowthHomeostasisHumanImmuneImmune systemImmunohistochemistryImmunotherapyIndividualInfiltrationLabelLasersLeadLearningLesionLigandsLightMalignant NeoplasmsMelanocytic nevusMelanoma CellModelingMole the mammalMolecularMorphologyMusMutationNatureNevi and MelanomasNevusNevus CellNormal tissue morphologyOncogenesOncogenicOperating SystemOperative Surgical ProceduresPTEN genePigmentsPlayPopulationPreventionPrevention approachProcessProductionRoleSeriesSignal PathwaySignaling MoleculeSkinSpottingsTestingTherapeuticbasecell typedifferential expressionexperimental studylive cell imagingloss of function mutationmathematical modelmelanocytemelanomamouse modelmutant mouse modelnovelnovel strategiespreventprogramsreceptorresponseself-renewalsenescencesingle-cell RNA sequencingspatiotemporalstatisticstherapy resistanttime usetranscriptometranscriptomicstumorultraviolet irradiation
项目摘要
Project Summary
Melanoma, a cancer that can be surgically cured when detected early, can be difficult to distinguish from
common, benign pigmented spots (nevi) that develop on human skin, a situation that leads to the unnecessary
excision of benign nevi and the failure to detect some evolving melanomas. Intriguingly, the most frequent
oncogenic mutation in melanoma—activation of BRAF—is also the cause of most nevi. Yet, unlike melanoma,
nevi spontaneously growth-arrest. The explanation has been attributed to “oncogene-induced senescence”,
but a variety of observations indicate that what holds nevi in check is not cell-autonomous senescence, but
rather reversible interactions among nevus cells, and between those cells and their environment. Such
interactions resemble the intra-lineage feedback mechanisms used by many normal tissues to achieve growth
control and size homeostasis. Using an inducible Braf-mutant mouse model, we recently made the observation
that nevi are not only composed of pigmented cells but also a novel melanocyte population that forms a “veil”
around the pigmented cells, consistent with the existence of lineage relationships that could underlie such a
feedback strategy.
In this project, we will investigate the role of these cell types in mouse models that produce both nevi and
melanoma, seeking to identify both the nature of growth control and the means by which melanoma cells
escape from it. We will integrate mathematical modeling to develop hypotheses that can explain the
spatiotemporal dynamics and spatial statistics of nevus and melanoma development in these models, including
potential bifurcations that account for the development of both nevi and melanoma in the same mouse. We will
use time-course single cell RNA-sequencing to identify potential positive and negative feedback regulators that
drive such models, and will carry out experiments to test model-based predictions concerning the roles that
such molecules play. Finally, we will investigate the phenomenon of spontaneous regression, which occurs
with both mouse and human nevi, for clues into how the immune system efficiently recognizes melanocyte
overgrowth. Such information will be useful in developing new prevention and therapeutic strategies for this
devastating disease.
项目摘要
黑色素瘤是一种在早期发现时可以手术治愈的癌症,
常见的良性色素斑(痣),在人类皮肤上发展,这种情况会导致不必要的
切除良性痣和未能检测到一些发展中的黑色素瘤。有趣的是,最常见的
黑色素瘤中的致癌突变-BRAF的激活-也是大多数痣的原因。然而,与黑色素瘤不同,
痣自发生长停止。这种解释被归因于“癌基因诱导的衰老”,
但各种观察表明,控制痣的不是细胞自主衰老,
痣细胞之间以及这些细胞与环境之间的相互作用是可逆的。等
相互作用类似于许多正常组织用来实现生长的谱系内反馈机制
控制和大小稳态。最近,我们使用一种可诱导的Braf突变小鼠模型,
痣不仅由色素细胞组成,而且还由一种新的黑素细胞群组成,
周围的色素细胞,与存在的血统关系,可能是这样一个一致的,
反馈策略
在这个项目中,我们将研究这些细胞类型在小鼠模型中的作用,
黑色素瘤,寻求确定生长控制的性质和黑色素瘤细胞
我们将整合数学建模,以开发可以解释
这些模型中痣和黑色素瘤发展的时空动态和空间统计,包括
在同一只小鼠中,痣和黑色素瘤的发展可能存在分歧。我们将
使用时程单细胞RNA测序来鉴定潜在的正反馈和负反馈调节因子,
驱动这些模型,并将进行实验,以测试基于模型的预测,
这样的分子发挥作用。最后,我们将研究自发回归现象,
为了寻找免疫系统如何有效识别黑素细胞的线索,
过度生长这些信息将有助于制定新的预防和治疗策略,
毁灭性的疾病
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Anand K Ganesan其他文献
Anand K Ganesan的其他文献
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{{ truncateString('Anand K Ganesan', 18)}}的其他基金
Identifying Therapeutic Targets for Stage III Melanoma
确定 III 期黑色素瘤的治疗靶点
- 批准号:
10520052 - 财政年份:2019
- 资助金额:
$ 42.83万 - 项目类别:
Identifying Therapeutic Targets for Stage III Melanoma
确定 III 期黑色素瘤的治疗靶点
- 批准号:
10299623 - 财政年份:2019
- 资助金额:
$ 42.83万 - 项目类别:
Identifying Therapeutic Targets for Stage III Melanoma
确定 III 期黑色素瘤的治疗靶点
- 批准号:
10064616 - 财政年份:2019
- 资助金额:
$ 42.83万 - 项目类别:
Uncovering the Origin and Growth Regulation of Melanocytic Nevi
揭示黑素细胞痣的起源和生长调节
- 批准号:
10013693 - 财政年份:2019
- 资助金额:
$ 42.83万 - 项目类别:
Identifying the Molecular Characteristics of Migrating Melanocytes in Vitiligo Skin
鉴定白癜风皮肤中迁移的黑素细胞的分子特征
- 批准号:
9510693 - 财政年份:2018
- 资助金额:
$ 42.83万 - 项目类别:
Identifying the Molecular Characteristics of Migrating Melanocytes in Vitiligo Skin
鉴定白癜风皮肤中迁移的黑素细胞的分子特征
- 批准号:
9762842 - 财政年份:2018
- 资助金额:
$ 42.83万 - 项目类别:
PAK Kinases Regulate Melanoma Chemoresistance and Metastasis
PAK 激酶调节黑色素瘤化疗耐药和转移
- 批准号:
9262324 - 财政年份:2013
- 资助金额:
$ 42.83万 - 项目类别:
Phosphoinositide Signaling Regulates Melanogenesis
磷酸肌醇信号调节黑色素生成
- 批准号:
8826025 - 财政年份:2013
- 资助金额:
$ 42.83万 - 项目类别:
PAK Kinases Regulate Melanoma Chemoresistance and Metastasis
PAK 激酶调节黑色素瘤化疗耐药和转移
- 批准号:
8716685 - 财政年份:2013
- 资助金额:
$ 42.83万 - 项目类别:
Phosphoinositide Signaling Regulates Melanogenesis
磷酸肌醇信号调节黑色素生成
- 批准号:
8628045 - 财政年份:2013
- 资助金额:
$ 42.83万 - 项目类别:
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