Elucidating the Role of SMAD4 in Colorectal Cancer
阐明 SMAD4 在结直肠癌中的作用
基本信息
- 批准号:10632149
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAwardBRAF geneBindingBinding SitesBioinformaticsBiological ModelsCancer EtiologyCancer ModelCarcinomaCell NucleusCessation of lifeChIP-seqColon CarcinomaColonic NeoplasmsColorectal CancerDNA BindingDNA Sequence AlterationDataDevelopmentDisseminated Malignant NeoplasmDysplasiaEnvironmentFoundationsFutureGene ExpressionGene TargetingGenesGeneticGenetic TranscriptionGenomeGoalsHyperplasiaInstitutionKineticsKnowledgeLaboratory ResearchLesionMADH4 geneMalignant NeoplasmsMapsMeasurementMeasuresMentorshipModelingMolecularMolecular TargetMusMutateMutationNeoplasm MetastasisNucleic Acid Regulatory SequencesOncogenicOrganoidsPathologyPathway interactionsPatientsPhasePlayPrognosisRUNX3 geneResearchResourcesRoleScienceShapesSignal PathwaySolid NeoplasmSystemTestingTissuesTrainingTransforming Growth Factor betaTranslatingTransplantationTumor SubtypeTumor Suppressor GenesTumor Suppressor ProteinsTumor TissueUnited StatesUniversitiesWNT Signaling PathwayWomanadenomaanticancer researchbeta catenincancer genomecancer therapycancer typeclinically relevantcolon cancer cell linecolon cancer patientscolon cancer progressioneffective therapyepigenomicsfortificationgain of functionin vivoinsightmenmouse modelmutantnovelpost-doctoral trainingprogramsrole modelscreeningskillstherapeutic targettooltranscription factortumortumor progressiontumorigenesis
项目摘要
Project Summary/Abstract
Colon cancer is the 2nd-leading cause of cancer-related deaths in the United States and is one of the best-
characterized solid tumors in terms of its common genetic mutations. However, knowledge gaps exist in the
basic understanding of these cancers downstream of their genetic profile. For instance, the tumor-suppressor
gene SMAD4 is mutated in approximately 57% of all colon tumors, and is associated with poor prognosis in
patients, yet there is still little understanding of its molecular mechanisms in colon cancer. Additionally,
while ~70% of colon cancers follow the typical WNT-driven adenoma-to-carcinoma pathway, approximately
20% follow the “serrated tumor pathway”- often driven by gain-of-function BRAF mutations and have the worst
prognosis of colon cancers. The proposal’s main objective will focus on elucidating the mechanistic role of
the tumor suppressor SMAD4 in colon cancers. The hypothesis is that SMAD4 plays a critical transcriptional
regulatory role in regulating the WNT pathway and is a key regulator in the serrated tumor pathway. The
rationale is based on preliminary studies that reveal: 1) that SMAD4 binds to regulatory regions of the genome
also bound by ß-catenin – the transcriptional effector of the most commonly mutated signaling pathway in
colon cancer, the WNT pathway; and 2) SMAD4 loss, when combined with activation of BRAF, can trigger
serrated tumor formation as rapidly as 1 month in mice. Aim 1 will use epigenomic approaches to map the
interaction of SMAD4 with ß-catenin at the level of DNA-binding - detailing the first intersection of these
pathways on the colon cancer genome. Aim 2 will use new mouse models to determine how SMAD4
suppresses the serrated cancer transition from hyperplastic lesions to dysplasias. Aim 3 will use state-of-the-
art tumor organoid model systems to determine how SMAD4 suppresses serrated cancer metastasis. The goal
is to test the hypotheses that 1) SMAD4 directly regulates the WNT-signaling pathway by redirecting ß-catenin
to tumor-suppressive gene targets in coordination with RUNX3, thus impacting cancer development, and 2)
that SMAD4 suppresses key signaling pathways that are required for serrated tumor progression and
metastasis. The proposed studies are significant in that they will identify the regulatory targets of a commonly
mutated tumor-suppressor gene and present a new perspective on an understudied, but more deadly, colon
cancer tumor type. These studies would have broad impacts in the cancer research field, and will reveal new
targets to identify and treat patients with serrated tumors. With the co-mentorship of Drs. Michael Verzi and
Ronald Hart, this proposal's training plan will prepare me for a transition to independence by 1) continuing to
enhance my epigenomics skillset, 2) develop novel model systems to address critical questions in the colon
cancer field, and 3) fortify the skills required to establish and maintain my own independent research program.
The Department of Genetics at Rutgers University has been an outstanding institution for my postdoctoral
training, and I will benefit greatly from the environment as I transition towards independence.
项目总结/摘要
结肠癌是美国癌症相关死亡的第二大原因,也是最好的癌症之一。
根据其常见的基因突变来表征实体瘤。然而,知识差距存在于
基本了解这些癌症的遗传特征下游。例如,肿瘤抑制因子
SMAD 4基因在大约57%的结肠肿瘤中发生突变,并且与结肠癌的预后不良相关。
患者,但仍然很少了解其在结肠癌中的分子机制。此外,本发明还
虽然约70%的结肠癌遵循典型的WNT驱动的腺瘤到癌的途径,
20%遵循“锯齿状肿瘤途径”-通常由功能获得性BRAF突变驱动,
结肠癌的预后。该提案的主要目标将侧重于阐明
结肠癌中的肿瘤抑制因子SMAD 4。假设SMAD 4在转录调控中起关键作用,
在调节WNT途径中具有调节作用,并且是锯齿状肿瘤途径中的关键调节剂。的
基本原理是基于初步研究,这些研究揭示:1)SMAD 4与基因组的调节区域结合
也被β-连环蛋白结合,β-连环蛋白是最常见的突变信号通路的转录效应子,
结肠癌,WNT通路; 2)SMAD 4丢失,当与BRAF激活结合时,可以触发
锯齿状肿瘤的形成在小鼠中快达1个月。Aim 1将使用表观基因组方法来绘制
SMAD 4与β-连环蛋白在DNA结合水平上的相互作用-详细描述了这些相互作用的第一个交叉点。
结肠癌基因组上的通路。Aim 2将使用新的小鼠模型来确定SMAD 4
抑制锯齿状癌从增生性病变向发育不良的转变。目标3将使用国家的-
本发明的肿瘤类器官模型系统以确定SMAD 4如何抑制锯齿状癌转移。目标
SMAD 4通过重定向β-连环蛋白直接调节WNT信号通路
与RUNX 3协调的肿瘤抑制基因靶点,从而影响癌症发展,以及2)
SMAD 4抑制锯齿状肿瘤进展所需的关键信号通路,
转移拟议的研究意义重大,因为它们将确定一种常见的
突变的肿瘤抑制基因,并提出了一个新的角度研究不足,但更致命的,结肠
癌症肿瘤类型这些研究将在癌症研究领域产生广泛的影响,并将揭示新的
以识别和治疗锯齿状肿瘤患者。在Michael Verzi博士和
罗纳德哈特,这个建议的训练计划将为我过渡到独立做好准备,1)继续
提高我的表观基因组学技能,2)开发新的模型系统来解决结肠中的关键问题
癌症领域,和3)加强所需的技能,建立和维护我自己的独立研究计划。
罗格斯大学遗传学系一直是我博士后的杰出机构
培训,我将大大受益于环境,因为我过渡到独立。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Kevin Tong其他文献
Kevin Tong的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Kevin Tong', 18)}}的其他基金
Elucidating the Role of SMAD4 in Colorectal Cancer
阐明 SMAD4 在结直肠癌中的作用
- 批准号:
10614758 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
Elucidating the Role of SMAD4 in Colorectal Cancer
阐明 SMAD4 在结直肠癌中的作用
- 批准号:
9977419 - 财政年份:2020
- 资助金额:
$ 24.9万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Research Grant














{{item.name}}会员




