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前沿研究。作为一名研究生，我的工作效率很高，发表了 5 篇第一作者论文（总共 10 篇）文件）。然后我从辛辛那提前往波特兰加入利斯凯博士的实验室。我曾经是一个博士后研究员工作了四年多，我在 Oncogene 和 Carcinogenesis 上发表了两篇第一作者论文。为了继续实现成为一名独立研究者的目标，我提议进行两年的癌症生物学指导研究，并接受高通量生物信息学、数学建模和异种移植方面的新培训。这个 K99 奖项不仅能让我继续我目前的工作，还能拓宽知识基础，这将帮助我成功创办自己的实验室，通过结合生物信息学、数学来解决癌症生物学领域的重要问题。癌症建模和小鼠模型。在培训期间，我将申请美国各地学术研究机构的独立终身职位。我的培训的一个组成部分涉及复杂的小鼠实验~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小鼠外科技术研讨会。我还希望参加杰克逊实验室的人类癌症小鼠模型技术研讨会。为了进一步培训，我将参加俄勒冈州立大学 Vollum 研究所提供的为期六周的写作课程。本课程旨在提高我的手稿和资助提案的写作水平。在我的指导培训期间，我将从三位具有广泛生物学背景的知名研究人员那里获得宝贵的研究技能和职业培训。我还计划选修 OHSU 提供的几门生物信息学课程。 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模型〜Spellman博士专门研究高通量生物信息学分析。广泛的培训将帮助我适应未来生物学领域的进步和变化。 OHSU 拥有出色的设施和资源来支持我的研究以及我在 K99/R00 奖项期间的职业发展。动物设施位于比较医学系的相邻大楼内，该系获得了实验动物护理评估和认证协会 (AAALAC) 的完全认证，并且保险函已在 NIH 动物实验室办公室存档福利（OLAW）。 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) 和大规模并行测序共享资源 (MPSSR)。 OHSU 是排名前 20 的研究机构，拥有广泛的资源来制定我的研究计划并实现我成为一名独立研究者的目标。当我转为独立研究者时，OHSU 分子和医学遗传学系致力于为我提供特殊的资源和培训机会。我在俄勒冈健康与科学大学的博士后培训重点是肠癌。我专注于使用一种新型的癌症小鼠模型，即 Pms2cre 小鼠。这种小鼠可以在正常细胞的背景下对基因进行分离的遗传操作，从而模仿散发性癌症。我的工作结果发表在 Oncogene 上，我发现逐步（遗传性癌症模型）和同时（散发性癌症模型）Apc 损失之间存在表型差异。这项工作很重要，因为它表明与散发性癌症相比，遗传性癌症通过不同的机制形成。我最近还在 Carcinogenesis 上发表了我的研究成果，其中我发现肠道腺瘤的形成需要一个临界大小的 Apc 缺陷隐窝区域来促进肿瘤的发生，重要的是，NSAIDs 通过阻断该区域的形成来起到化学预防腺瘤形成的作用。这项 K99 提案延续了我对 Pms2cre 小鼠模型和肠道 Apc 丢失的研究，同时还解决了化学预防问题，并使用不同的小鼠模型、类器官培养和异种移植物来进一步了解从正常到转化的转变。该提案的长期目标是了解关键抑癌基因和癌基因突变后肠道干细胞从正常细胞向肿瘤细胞的转变。这一目标将通过使用几种不同的小鼠模型、肠道类器官和异种移植物来实现。具体来说，我将研究遗传 Apc 缺陷的隐匿性进展途径，从而导致有效的肿瘤起始（目标 1）。在进行这些研究的同时，我将研究 Apc 突变和舒林酸对肠道干细胞中性漂移的影响（目标 2）。同时，我将研究 Apc 缺陷的动态培养的“小肠”和人类癌细胞系衍生的异种移植物中的肠细胞（目标 3）。肠癌是美国第三大癌症原因，这项研究将帮助我们了解其发生、进展和预防的根本原因。