Cancer and Stem Cell Dynamics in the Intestine

肠道中的癌症和干细胞动力学

基本信息

批准号：
8881124
负责人：
Jared Michael Fischer
金额：
$ 10.18万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8881124
关键词：
APC gene Accreditation Address Adenomatous Polyposis Coli Affect Applications Grants Aspirin Award Bioinformatics Biological Biology Biometry Cancer Biology Cancer Etiology Cancer Model Cancer cell line Cells Cessation of life Chemoprevention Chemopreventive Agent Chronic Colon Carcinoma Colorectal Cancer Complex Core Facility DNA Sequence Development Dose Drug Design Educational workshop Epithelial Cells Event Exhibits Flow Cytometry Future Genes Genetic Genetic study Goals Health Health Sciences Histopathology Human Individual Inherited Institutes Institution Insurance Intestinal Cancer Intestines Laboratories Laboratory Animals Laboratory mice Lead Letters Malignant Neoplasms Manuscripts Massive Parallel Sequencing Medical Genetics Medicine Mentors Modeling Molecular Genetics Mus Mutate Mutation Neoplasm Metastasis Non-Steroidal Anti-Inflammatory Agents Normal Cell Oncogenes Oncogenic Operative Surgical Procedures Oregon Organoids Outcome Paper Pathology Pathway interactions Patients Phase Phenotype Play Positioning Attribute Postdoctoral Fellow Prevention Primary Neoplasm Process Publishing Research Research Institute Research Personnel Resource Sharing Resources Signal Transduction Social Welfare Staging Stem cells Sulindac Techniques Testing The Jackson Laboratory Therapeutic Training Travel Tumor Initiators Tumor Suppressor Genes United States United States National Institutes of Health Universities Woman Work Writing Xenograft procedure adenoma animal care animal facility cancer cell cancer genome cancer initiation cancer prevention cancer risk cancer stem cell carcinogenesis career career development cell type comparative design drug efficacy exome genetic makeup genetic manipulation graduate student in vivo insight intestinal crypt knowledge base lifetime risk mathematical model men mouse model novel novel strategies outcome forecast post-doctoral training research study skills stem cell biology tumor tumor initiation tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): My ultimate career goal is to become an independent investigator at an academic institution and perform cutting edge research in the field of cancer biology. As a graduate student, I was highly productive, publishing 5 first author papers (10 total papers). I then traveled from Cincinnati to Portland to join Dr. Liskay's laboratory. I have been a postdoctoral fellow for just over 4 years and I have published two first author papers in Oncogene and Carcinogenesis. To continue toward my goal of becoming an independent investigator, I have proposed two years of mentored research in cancer biology with new training in high- throughput bioinformatics, mathematical modeling and xenografts. This K99 award will allow me to not only continue my current work, but also broaden the base of knowledge, which will help me to successfully start a lab of my own that can address important questions in the field of cancer biology by combining bioinformatics, mathematical modeling and mouse models of cancer. During my training, I will be applying for independent tenure-track positions at academic research institutes throughout the United States. An integral part of my training involves complex experimentation with mice~ therefore, as part of my training I plan to attend the Workshop on Surgical Techniques in the Laboratory Mouse offered at the Jackson Laboratory. I also hope to attend the Workshop on Techniques in Modeling Human Cancer in Mice at the Jackson Laboratories. To further my training, I will take a six-week writing course offered by the Vollum Institute at OHSU. This course is designed to enhance my writing of both manuscripts and grant proposals. During my mentored training, I will gain valuable research skills and career training from three well established researchers with a broad spectrum of biological backgrounds. I also plan to take several courses on Bioinformatics offered at OHSU. Dr. Liskay specializes in colon cancer and mutation~ Dr. Shibata specializes in colon cancer, mathematical modeling of stem cell biology and pathology~ and Dr. Spellman specializes in high-throughput bioinformatic analyses. The breadth of training will help make me adaptable in the future as the field of biology advances and changes. OHSU has outstanding facilities and resources available to support my research as well as my career development throughout the K99/R00 award. Animal facilities are located in an adjacent building in the Department of Comparative Medicine, which has full accreditation from the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC), and letters of insurance are on file with the NIH in the Office of Animal Laboratory Welfare (OLAW). OHSU also offers a variety of core facilities including flow cytometry/FACS, DNA sequencing, Histopathology and Biostatistics. In particular, I will be using the Gene Profiling Shared Resource (GPSR) and the Massively Parallel Sequencing Shared Resource (MPSSR). OHSU is a top-20 research institute with a wide range of resources to both develop my research plan and pursue my goal of being an independent investigator. The Department of Molecular and Medical Genetics at OHSU is committed to providing exceptional resources and training opportunities to me as I transitions to an independent investigator. My postdoctoral training at Oregon Health and Science University is focused on intestinal cancer. I have concentrated on using a novel mouse model of cancer, the Pms2cre mouse. This mouse allows for the isolated, genetic manipulation of genes in a background of normal cells, thus mimicking sporadic cancer. The results of my work were published in Oncogene where I found a phenotypic difference between stepwise (model of inherited cancer) and simultaneous (model of sporadic cancer) Apc loss. This work was important because it suggested that inherited cancer forms via a different mechanism compared to sporadic cancer. I also recently published my work in Carcinogenesis, where I found that intestinal adenoma formation requires a critical sized field of Apc-deficient crypts for tumor initiation and importantly that NSAIDs work as a chemopreventive of adenoma formation by blocking the formation of this field. This K99 proposal continues my work with the Pms2cre mouse model and Apc loss in the intestine, while also addressing issues with chemoprevention and using different mouse models, organoid culture and xenografts to further understand the transition from normal to transformed. The long term objectives of this proposal are to understand the transition of an intestinal stem cell from normal to tumor following mutation in key tumor suppressors and oncogenes. This objective will be achieved by using several different mouse models, intestinal organoids and xenografts. Specifically, I will study the genetic pathways of Apc-deficient occult progression, which results in efficient tumor initiation (Aim 1). While these studies are happening, I will study the effects of Apc mutation and sulindac on intestinal stem cell neutral drift (Aim 2). In parallel, I will study the dynamics of Apc-deficient intestinal cells in cultured "miniguts" and human cancer cell line derived xenografts (Aim 3). Intestinal cancer is the third leading cause of cancer in the United States and this research will help us understand the fundamental causes of its initiation, progression and prevention.

描述（由申请人提供）：我的最终职业目标是成为学术机构的独立研究者，并在癌症生物学领域进行尖端研究。作为一名研究生，我的生产力很高，发表了5篇第一篇论文（总共10篇文件）。然后，我从辛辛那提前往波特兰加入Liskay博士的实验室。我一直是博士后研究员已有4年多了，我发表了两篇关于癌基因和致癌作用的第一篇作者论文。为了继续成为一名独立研究者的目标，我提出了两年的指导癌症生物学研究，并在高吞吐物生物信息学，数学建模和异种移植物方面进行了新的培训。这个K99奖将使我不仅可以继续我当前的工作，还可以扩大知识的基础，这将帮助我成功启动自己的实验室，可以通过结合生物信息学，数学建模和癌症的老鼠模型来解决癌症生物学领域的重要问题。在我的培训期间，我将在美国的学术研究机构申请独立的终身职位。我的培训中不可或缺的一部分涉及对小鼠进行复杂的实验。因此，作为我培训的一部分，我计划参加杰克逊实验室提供的实验室鼠标手术技术研讨会。我也希望参加杰克逊实验室中的小鼠对人类癌症建模技术的研讨会。为了进一步培训，我将参加OHSU Vollum Institute提供的六周写作课程。本课程旨在增强我对手稿和赠款建议的写作。在我的指导培训中，我将从拥有广泛生物学背景的三位知名研究人员那里获得宝贵的研究技能和职业培训。我还计划在OHSU提供几门关于生物信息学的课程。 Liskay博士专门研究结肠癌和突变〜Shibata博士专门研究结肠癌，干细胞生物学和病理学的数学建模〜和Spellman博士专门研究高通量生物信息学分析。随着生物学的进步和变化领域，培训的广度将有助于使我在将来适应。 OHSU拥有出色的设施和资源来支持我的研究以及整个K99/R00奖的职业发展。动物设施位于比较医学系的相邻建筑物中，该建筑物获得了实验室动物护理评估和认证协会（AAAALAC）的全面认证，保险书将与NIH一起在动物实验室福利办公室（Olaw）中。 OHSU还提供各种核心设施，包括流式细胞术/FACS，DNA测序，组织病理学和生物统计学。特别是，我将使用基因分析共享资源（GPSR）和大量并行测序共享资源（MPSSR）。 OHSU是拥有大量资源的前20名研究所，可以制定我的研究计划，并追求成为独立研究者的目标。 OHSU的分子和医学遗传学系致力于在我向独立研究者过渡时为我提供非凡的资源和培训机会。我在俄勒冈州健康与科学大学的博士后培训专注于肠癌。我专注于使用新型的癌症模型PMS2CRE小鼠。该小鼠允许在正常细胞的背景下对基因进行分离，基因操纵，从而模仿零星癌。我的工作结果发表在癌基因中，我发现逐步（遗传癌的模型）和同时（零星癌的模型）APC损失之间存在表型差异。这项工作很重要，因为它建议与零星癌相比，通过不同的机制遗传了癌症形式。我最近还发表了我在致癌作用方面的工作，在那里我发现肠道腺瘤的形成需要一个临界大小的APC缺陷型隐窝范围来进行肿瘤的启动，并且重要的是，NSAIDS可以通过阻止该领域的形成来充当化学预防腺瘤形成的化学预防。该K99提案继续我使用肠道PMS2CRE小鼠模型和APC损失的工作，同时还解决了化学预防的问题，并使用不同的小鼠模型，类器官培养和异种移植物，以进一步了解从正常到转化的过渡。该提案的长期目标是了解关键肿瘤抑制剂和癌基因中突变后肠道干细胞从正常到肿瘤的过渡。该目标将通过使用几种不同的小鼠模型，肠道器官和异种移植物来实现。具体来说，我将研究遗传 APC缺陷的神秘进展的途径，导致有效的肿瘤起始（AIM 1）。在进行这些研究时，我将研究APC突变和苏琳克对肠道干细胞中性漂移的影响（AIM 2）。同时，我将研究APC缺陷的动力学培养的“小型”和人类癌细胞系中的肠细胞衍生出异种移植物（AIM 3）。肠癌是美国癌症的第三主要原因，这项研究将有助于我们了解其起始，进展和预防的基本原因。