EPIMORPHIN DELETION ALTERS STEM CELL NICHE MYOFIBROBLAST SECRETION
表吗啡缺失改变干细胞微环境肌成纤维细胞分泌
基本信息
- 批准号:8472459
- 负责人:
- 金额:$ 16.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-01 至 2017-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdvisory CommitteesAwardAzoxymethaneBone MarrowBone Marrow CellsBone Morphogenetic ProteinsCancer ModelCell ProliferationCellsCellular biologyChimera organismClinicalCoculture TechniquesColitisColon CarcinomaColorectal CancerCommitComplicationCrohn&aposs diseaseDevelopmentDevelopment PlansDockingDysplasiaEnvironmentEpithelialEpithelial Cell ProliferationEpithelial-Stromal CommunicationEventFamilyFlow CytometryFundingGastroenterologyGenerationsGoalsGroup MeetingsImmuneIndividualInflammationInflammatoryInflammatory Bowel DiseasesInjuryInpatientsInstructionInterleukin-6IntestinesLabelMalignant NeoplasmsManuscriptsMedicineMentorsModelingMolecularMorphogenesisMusMyofibroblastPathogenesisPhenotypePhysiciansPlayProteinsPublishingRegulationResearchResearch Project GrantsResearch ProposalsResourcesRoleScientistSignaling MoleculeSodium Dextran SulfateStromal CellsTechnical ExpertiseTimeTrainingTransplantationTumor BurdenUlcerative ColitisUniversitiesVesicleWashingtonbasecareercareer developmentchordincolitis associated cancercrypt cellcytokineepimorphinin vivoinhibitor/antagonistlaser capture microdissectionmacrophagemedical schoolsmeetingsmembernovel therapeutic interventionprofessorstem cell nichesymposiumsyntaxin
项目摘要
DESCRIPTION (provided by applicant): As an Assistant Professor of Medicine in the Division of Gastroenterology at Washington University School of Medicine, I am focused on exploring mechanisms whereby deletion of a myofibroblast protein results in protection from colitis and colitis associated cancer (CAC). Immediate and long-term career goals: This award will allow time to obtain didactic training and technical expertise, and publish additional first-authored manuscripts detailing the role of the stroma and colonic myofibroblast in the development of CAC, with the goal of applying for independent funding in the form of an R01 in year 4 of this award. In the long-term I hope to transition to an independent investigative career as a physician-scientist in gastroenterology, investigating the stroma in the pathogenesis of inflammation associated cancer. Career development: Inpatient clinical duties are limited to < 25% of my time. In addition to completing the aims of my research proposal, my career development plan consists of individual and group meetings with mentors Drs. Rubin and Newberry, meetings with my Advisory Committee, conferences in the GI Division and the School of Medicine, participation in national conferences including DDW, FASEB, and AAI, and instruction in bone marrow transfer, flow cytometry, and laser capture microdissection. I plan on completing Aim 1 studies and detailing my findings in a manuscript by the end of year 1; completing a substantial portion of Aim 2 along with a manuscript by years 2-3; and completing Aim 2 studies and a manuscript in years 4-5. Environment: The research and educational resources of Washington University School of Medicine and the Gastroenterology Division have contributed to the generation of successful physician-scientists. My mentors Drs. Rubin and Newberry are well-established experts in stromal/epithelial and immune cellular biology and have committed to providing training for the proposed research project. Research: Disrupted epithelial-stromal interactions are implicated in the pathogenesis of colitis and CAC. Epimorphin (epim) is a stromal and myofibroblast protein that regulates intestinal epithelial morphogenesis. Epim-/- mice are partially protected from acute colitis in association with an increase in crypt cell proliferation. We have shown in a murine model of CAC that Epim-/- mice have markedly reduced dysplastic tumor burden. We have also demonstrated that epimorphin deletion increases secretion of Chordin from colonic myofibroblasts and decreases secretion of Interleukin-6 (IL-6) from myofibroblasts and macrophages. We propose that these regulatory events are important because Chordin inhibits bone morphogenetic protein (Bmp), a protein known to inhibit crypt cell proliferation. In addition, IL-6 is a pro-inflammatory cytokine that has been implicated in CAC. These observations underlie our two major hypotheses: Hypothesis 1: Epimorphin deletion alters colonic myofibroblast secretion of key signaling molecules that regulate crypt cell proliferation (Bmps and Bmp inhibitors) and modulate inflammation (cytokines). Hypothesis 2: Epimorphin deletion alters the secretory function of bone marrow derived myofibroblasts and stromal cells which play a significant role in conferring protection from colitis and CAC. These related hypotheses will be pursued in the following specific aims: 1. Determine the mechanisms by which epimorphin deletion results in an increase in epithelial crypt cell proliferation and reduced inflammation. These studies will address hypothesis 1. We will use Epim-/- and WT myofibroblasts and myofibroblast-epithelial co-cultures to examine the effect of epimorphin deletion on colonic myofibroblast secretion of signaling molecules involved in the regulation of crypt cell proliferation (Bmps) and inflammation (cytokines). We will extend these observations to the dextran sodium sulfate (DSS) colitis and azoxymethane (AOM)/DSS CAC models. We predict epimorphin deletion will alter myofibroblast secretion of Bmps and cytokines to increase epithelial cell proliferation and reduce inflammation. 2. Define the identity and origin of the cells that are responsible for protection from DSS colitis and AOM/DSS CAC in Epim-/- mice. These studies will address hypothesis 2. Myofibroblasts are resident in the intestinal stroma but in the setting of injury or inflammation, "new" myofibroblasts and other bone marrow (BM) derived stromal cells migrate into the intestine. To determine whether the observed phenotype in Epim-/- mice is a consequence of BM derived cells, we will perform GFP labeled Epim-/- and WT BM rescue of lethally irradiated Epim-/- and WT recipients and treat BM chimeras with DSS and AOM/DSS. We will determine the cellular identify of the transplanted BM cells in the recipient and define their cytokine secretory profile. We predict that Epim-/- BM donor derived cells will be required to achieve maximal protection from DSS colitis and AOM/DSS dysplasia. These studies may provide the basis for novel therapeutic approaches to inflammatory bowel disease and CAC.
描述(由申请人提供):作为华盛顿大学医学院消化病学部门的医学助理教授,我专注于探索肌成纤维细胞蛋白缺失导致结肠炎和结肠炎相关癌症(CAC)保护的机制。近期和长期职业目标:该奖项将允许时间获得教学培训和技术专长,并发表更多的第一作者手稿,详细说明基质和结肠肌成纤维细胞在CAC发展中的作用,目标是在该奖项的第4年以R01的形式申请独立资金。从长远来看,我希望过渡到一个独立的研究事业作为一个内科科学家在胃肠病学,研究间质在炎症相关癌症的发病机制。职业发展:住院临床工作时间限制在25%以下。除了完成我的研究计划的目标外,我的职业发展计划还包括与导师dr。Rubin和Newberry,与我的顾问委员会的会议,GI部门和医学院的会议,参加包括DDW, FASEB和AAI在内的国家会议,以及骨髓移植,流式细胞术和激光捕获显微解剖的指导。我计划在第一学年结束前完成第一阶段的研究,并在一份手稿中详细介绍我的发现;在第2-3年完成目标2的大部分以及一份手稿;并在第4-5年完成第二阶段的研究和一篇论文。环境:华盛顿大学医学院和胃肠病学部门的研究和教育资源为一代成功的内科科学家做出了贡献。我的导师博士。Rubin和Newberry是间质/上皮和免疫细胞生物学方面的知名专家,并致力于为拟议的研究项目提供培训。研究:破坏上皮间质相互作用与结肠炎和CAC的发病机制有关。Epimorphin (epim)是一种调节肠上皮形态发生的间质和肌成纤维细胞蛋白。Epim-/-小鼠对急性结肠炎的部分保护与隐窝细胞增殖的增加有关。我们已经在小鼠CAC模型中表明,Epim-/-小鼠显著减少了发育不良肿瘤的负担。我们还证明,表imorphin缺失增加了结肠肌成纤维细胞分泌Chordin,减少了肌成纤维细胞和巨噬细胞分泌白细胞介素-6 (IL-6)。我们认为这些调节事件是重要的,因为Chordin抑制骨形态发生蛋白(Bmp),一种已知的抑制隐窝细胞增殖的蛋白。此外,IL-6是一种与CAC有关的促炎细胞因子。这些观察结果支持了我们的两个主要假设:假设1:表imorphin缺失改变了结肠肌成纤维细胞分泌调节隐窝细胞增殖(Bmp和Bmp抑制剂)和调节炎症(细胞因子)的关键信号分子。假设2:表imorphin缺失改变了骨髓来源的肌成纤维细胞和基质细胞的分泌功能,这些细胞在保护结肠炎和CAC中起着重要作用。这些相关的假设将在以下具体目标中进行:确定表啡肽缺失导致上皮隐窝细胞增殖增加和炎症减少的机制。这些研究将解决假设1。我们将使用Epim-/-和WT肌成纤维细胞和肌成纤维细胞-上皮共培养来检测epimorphin缺失对结肠肌成纤维细胞分泌参与隐窝细胞增殖(Bmps)和炎症(细胞因子)调节的信号分子的影响。我们将这些观察结果扩展到葡聚糖硫酸钠(DSS)结肠炎和偶氮甲烷(AOM)/DSS CAC模型。我们预测表orphin的缺失会改变肌成纤维细胞Bmps和细胞因子的分泌,从而增加上皮细胞的增殖并减少炎症。2. 确定Epim-/-小鼠中负责保护DSS结肠炎和AOM/DSS CAC的细胞的身份和来源。这些研究将解决假设2。肌成纤维细胞存在于肠间质中,但在损伤或炎症的情况下,“新的”肌成纤维细胞和其他骨髓来源的间质细胞迁移到肠中。为了确定Epim-/-小鼠中观察到的表型是否是BM来源细胞的结果,我们将对致命辐照的Epim-/-和WT受体进行GFP标记的Epim-/-和WT BM拯救,并用DSS和AOM/DSS治疗BM嵌合体。我们将确定受体移植骨髓细胞的细胞鉴定,并确定其细胞因子分泌谱。我们预测Epim-/- BM供体来源的细胞将需要获得最大的保护,以防止DSS结肠炎和AOM/DSS发育不良。这些研究可能为炎症性肠病和CAC的新治疗方法提供基础。
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 }}
Anisa Shaker其他文献
Anisa Shaker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('Anisa Shaker', 18)}}的其他基金
The role of esophageal myofibroblasts in alcohol related esophageal squamous cell carcinoma.
食管肌成纤维细胞在酒精相关食管鳞状细胞癌中的作用。
- 批准号:
10371074 - 财政年份:2021
- 资助金额:
$ 16.15万 - 项目类别:
The role of human esophageal myofibroblasts in regulating the epithelial response in GERD
人食管肌成纤维细胞在调节 GERD 上皮反应中的作用
- 批准号:
10017196 - 财政年份:2019
- 资助金额:
$ 16.15万 - 项目类别:
The role of human esophageal myofibroblasts in regulating the epithelial response in GERD
人食管肌成纤维细胞在调节 GERD 上皮反应中的作用
- 批准号:
10170345 - 财政年份:2019
- 资助金额:
$ 16.15万 - 项目类别:
The role of human esophageal myofibroblasts in regulating the epithelial response in GERD
人食管肌成纤维细胞在调节 GERD 上皮反应中的作用
- 批准号:
10623225 - 财政年份:2019
- 资助金额:
$ 16.15万 - 项目类别:
The role of human esophageal myofibroblasts in regulating the epithelial response in GERD
人食管肌成纤维细胞在调节 GERD 上皮反应中的作用
- 批准号:
10403963 - 财政年份:2019
- 资助金额:
$ 16.15万 - 项目类别:
Epithelial-stromal cross-talk in esophageal inflammation and carcinogenesis.
食管炎症和癌变中的上皮-基质相互作用。
- 批准号:
8959570 - 财政年份:2015
- 资助金额:
$ 16.15万 - 项目类别:
EPIMORPHIN DELETION ALTERS STEM CELL NICHE MYOFIBROBLAST SECRETION
表吗啡缺失改变干细胞微环境肌成纤维细胞分泌
- 批准号:
8292005 - 财政年份:2011
- 资助金额:
$ 16.15万 - 项目类别:
EPIMORPHIN DELETION ALTERS STEM CELL NICHE MYOFIBROBLAST SECRETION
表吗啡缺失改变干细胞微环境肌成纤维细胞分泌
- 批准号:
9004607 - 财政年份:2011
- 资助金额:
$ 16.15万 - 项目类别:
EPIMORPHIN DELETION ALTERS STEM CELL NICHE MYOFIBROBLAST SECRETION
表吗啡缺失改变干细胞微环境肌成纤维细胞分泌
- 批准号:
8604226 - 财政年份:2011
- 资助金额:
$ 16.15万 - 项目类别:
EPIMORPHIN DELETION ALTERS STEM CELL NICHE MYOFIBROBLAST SECRETION
表吗啡缺失改变干细胞微环境肌成纤维细胞分泌
- 批准号:
8111337 - 财政年份:2011
- 资助金额:
$ 16.15万 - 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:
$ 16.15万 - 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:
$ 16.15万 - 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:
$ 16.15万 - 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:
$ 16.15万 - 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:
$ 16.15万 - 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:
$ 16.15万 - 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:
$ 16.15万 - 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:
$ 16.15万 - 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:
$ 16.15万 - 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:
$ 16.15万 - 项目类别:
Research Grant