Role of LIN28B in the regulation of intestinal epithelial growth

LIN28B在肠上皮生长调节中的作用

• 批准号: 8382981
• 负责人: Blair Bernard Madison
• 金额: $ 11.24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8382981
• 关键词: Advisory Committees; Affect; Apoptosis; Award; Binding; Binding Sites; Biochemical; Bioethics; Bioinformatics; Biology; Biometry; Caco-2 Cells; Cell Line; Cell Maintenance; Cell Proliferation; Cell division; Cells; Chromatin; Colon; Data; Dependence; Development; Digestive System Disorders; Disease; Enteral; Epithelial; Epithelium; Equilibrium; Event; Fostering; Gastroenterology; Gene Targeting; Grant; Growth; Hallmark Cell; Homeostasis; Immunohistochemistry; Immunoprecipitation; In Vitro; Individual; Infection; Inflammatory Bowel Diseases; Injury; International; Intestines; Journals; Life; Link; Liver; Liver diseases; Lung; MYC Family Protein; Maintenance; Malignant Neoplasms; Manuscripts; Measures; Mentorship; Messenger RNA; Mitotic; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Neoplasms; Oncogenes; Ovary; Phenotype; Play; Preparation; Process; Prostate; Proteins; RNA; Regulation; Research; Ribonucleoproteins; Ribosomes; Role; Scientist; Series; Stem cells; Testing; Time; Training; Transcript; Transgenic Mice; United States National Institutes of Health; Villus; Visit; Western Blotting; Work; cancer stem cell; career; career development; cell growth; cell growth regulation; combinatorial; crosslink; crypt cell; in vivo; insight; intestinal crypt; intestinal epithelium; mRNA Stability; malignant breast neoplasm; meetings; migration; novel; particle; professor; progenitor; promoter; ranpirnase; skills; small hairpin RNA; stem cell niche; symposium; transcription factor

DESCRIPTION (provided by applicant): Through the proposed training in his K01, I will pursue the additional mentorship that I need and the additional research time to enhance my passion for intestinal epithelial biology. During this award period I will have the opportunity to acquire and refine fundamental skills of becoming a developed scientist. Career development will be fostered through twice-weekly meetings with Dr. Rustgi, convening an expert interdisciplinary advisory committee twice annually, and taking advantage of opportunities in career and professional development through UPenn, the NIH and the AGA. These skills include (but are not limited to) manuscript and grant preparation, lab meeting presentations, participation in the seminars and courses described herein, and presentations at international research conferences (DDW, Keystone). Training will also entail course-work in biostatistics (two semesters), short courses in RNA biology and basic bioinformatics, ongoing training in bioethics, weekly participation in the seminar series (where I will meet visiting professors), journal clubs (presentations semi-annually), and twice yearly floo lab meetings through the NIDDK P30 Center for Molecular Studies in Digestive and Liver Diseases and Division of Gastroenterology. The overarching hypothesis of this project is the following: LIN28B plays a critical role in regulating growth and proliferation in the intestinal epithelium via cooperation with c-MYC, with key roles for intestine stem cell (ISC) maintenance. Two potential interrelated mechanisms will be explored: 1) LIN28B binds to target mRNAs associated with cellular growth and cooperates with the transcription factor c-MYC, which is a master regulator of cell growth. and 2) LIN28B affects the maintenance of the ISC by promoting stem cell identity and growth. LIN28B is normally expressed in the intestinal epithelial crypt where cell division occurs. LIN28B represses the maturation of miRNAs such as Let-7, which is restricted to villus epithelium, where post- mitotic differentiated cells are located. The spatial restriction of LIN28B and Let-7 expression in the intestinal epithelium is likely crucial for maintaining sufficient but limited compartments of differentiation and proliferation. C-MYC is also restricted to the crypt epithelium and is required for epithelial proliferation and growth. W have evidence to support a Let-7-independent function of LIN28B entailing intimate cooperation with c-MYC. The Specific Aims of this proposal to test the hypothesis are the followin: 1) We will explore the functional relationship between LIN28B and c-MYC, in vitro. 2) We will assess how LIN28B cooperates with c-MYC through in vivo studies of Lin28b in the intestinal epithelium. 3) We will examine the potential of LIN28B to modulate the intestinal stem cell compartment. LIN28B function may be relevant to ISC homeostasis and epithelial proliferation. Determining how LIN28B functions in the intestinal crypt will likely provide an important link among the cellular mechanisms governing epithelial proliferation, differentiation, and/or mucosal regeneration. PUBLIC HEALTH RELEVANCE: This project will explore the regulation of cell growth in the lining of the intestine in stem cells and other dividing cells. Stem cells are required to constanly replenish cells of the intestinal lining throughout the entire life of an individual. This study wll provide key insights into how intestinal cell growth is maintained, controlled, and perturbed in disease states.

描述（由申请人提供）：通过在他的K01拟议的培训，我将追求我需要的额外导师和额外的研究时间，以提高我对肠上皮生物学的热情。 在这个奖项期间，我将有机会获得和完善成为一个发达的科学家的基本技能。 职业发展将通过每周两次与Rustgi博士的会议，每年两次召集专家跨学科咨询委员会，并通过UPenn，NIH和阿加利用职业和专业发展的机会来促进。 这些技能包括（但不限于）手稿和补助金准备，实验室会议演示，参加本文所述的研讨会和课程，以及在国际研究会议（DDW，Keystone）上的演讲。 培训还将包括生物统计学课程（两个学期）、RNA生物学和基础生物信息学短期课程、生物伦理学持续培训、每周参加系列研讨会（我将参加 将会见客座教授），期刊俱乐部（每半年一次的演讲），以及通过NIDDK P30消化和肝病分子研究中心和胃肠病学分部每年两次的floo实验室会议。 该项目的总体假设如下：LIN28 B通过与c-MYC合作在调节肠上皮细胞的生长和增殖中起关键作用，对肠干细胞（ISC）的维持起关键作用。 将探索两种潜在的相互关联的机制：1）LIN28 B结合与细胞生长相关的靶mRNA，并与转录因子c-MYC合作，c-MYC是细胞生长的主要调节因子。和2）LIN28 B通过促进干细胞身份和生长影响ISC的维持。 LIN28 B通常在发生细胞分裂的肠上皮隐窝中表达。 LIN28 B抑制miRNA如Let-7的成熟，其限于绒毛上皮，有丝分裂后分化的细胞位于绒毛上皮。 空间 肠上皮中LIN 28 B和Let-7表达的限制对于维持足够但有限的分化和增殖区室可能是至关重要的。 C-MYC也限于隐窝上皮，并且是上皮增殖和生长所需的。 我们有证据支持LIN28B的Let-7独立功能，需要与c-MYC密切合作。 本研究的具体目的是：1）在体外研究LIN28B与c-MYC的功能关系。 2)我们将通过对肠上皮中Lin28b的体内研究来评估LIN28B如何与c-MYC合作。 3)我们将研究LIN28 B调节肠干细胞区室的潜力。 LIN28 B功能可能与ISC稳态和上皮增殖有关。 确定LIN28B在肠隐窝中的功能可能会提供一个重要的联系，上皮细胞增殖，分化和/或粘膜再生的细胞机制。 公共卫生相关性：这个项目将探索在干细胞和其他分裂细胞的肠衬里细胞生长的调节。 干细胞需要不断地补充细胞的肠内膜在整个生命的一个人。 这项研究将提供关键的见解如何维持，控制和疾病状态下肠细胞的生长受到干扰。