Mechanisms modulating cell identity in regenerative mammalian epithelia

再生哺乳动物上皮细胞身份的调节机制

基本信息

批准号：
10534207
负责人：
Kara Lavidge McKinley
金额：
$ 15.95万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10534207
关键词：
Address Adopted Aging Antineoplastic Agents Architecture Award Back Biochemistry Cell Lineage Cell division Cells Cellular Morphology Cellular biology Cues Data Development Disease Endometrial Endometrial Carcinoma Endometrium Environment Epithelium Estrogens Exhibits Goals Health Homeostasis Hormone Responsive Hormones Human Human body Image Impairment In Vitro Individual Infection Injury Intestines Laboratories Longevity Mammals Menstrual cycle Menstruation Mentors Modeling Molecular Mus Natural regeneration Organ Organ Culture Techniques Organoids Ovarian Steroid Hormone Paneth Cells Pathway interactions Patients Phase Physiology Postdoctoral Fellow Process Progesterone Recovery Regenerative Medicine Regenerative research Regulation Reproductive Biology Research Signal Transduction Small Intestines Study models System Tamoxifen Technology Testing Time Tissues Training Translating Trauma WNT Signaling Pathway Work adult stem cell arm base cancer risk career development cell injury cell type endometrial organoid experience functional restoration imaging approach in vivo injured innovation irradiation malignant breast neoplasm mechanical signal mouse genetics platform-independent programs regenerative regenerative tissue repaired reproductive response response to injury skills stem cell therapy stem cells therapy development tissue regeneration tissue repair tool

项目摘要

PROJECT SUMMARY: Significance: Our tissues experience frequent damage from injuries, infections and disease. Many organs in the human body can undergo self-repair to restore their function after damage. This recovery is accomplished through the actions of adult stem cells, which generate new cells of diverse types to replace damaged material. The capacity of adult stem cells to repair tissues makes them an appealing target for the development of therapies to restore the health of tissues that have been impaired by injury or aging. However, much remains unknown about how stem cell progeny adopt appropriate cell fates to repopulate tissues. This Pathway to Independence Award proposal seeks to understand the mechanisms that generate specific cell types in regenerative mammalian tissues. Candidate and environment: The candidate for this Pathway to Independence Award, Dr. Kara McKinley, is committed to leading an independent research group at the interface of cell biology and regenerative medicine. Dr. McKinley was trained in cell biology and biochemistry in the laboratory of Dr. Iain Cheeseman at MIT, where she uncovered mechanisms required for the assembly and regulation of the cell division machinery. During her postdoctoral studies at UCSF in the laboratory of renowned cell biologist Dr. Ron Vale, she has developed approaches for long-term live imaging of organoids, which are “mini-organ” culture systems that mimic the cellular composition, architecture and responses of organs outside of the body. As described in this proposal, she will apply her organoid imaging approaches, combined with the targeted application of defined signals, to understand how extrinsic cues alter cell identity in two highly regenerative tissues: the small intestine (Aim 1), and the uterine lining (endometrium; Aim 2). Career development: During the mentored period, the candidate will gain additional training in mouse genetics to translate her findings from in vitro organoid systems into in vivo contexts, and in reproductive biology to translate her approaches from small intestinal organoids to endometrial organoids. Combining studies of the small intestine and the endometrium presents a unique and powerful platform for her independent group to apply common tools and approaches to reveal unifying features of regeneration, as well as to identify key aspects of organ-specific physiology. The candidate will work with experts in mouse genetics and reproductive biology at UCSF to build the necessary scientific skills to propel her research in these two complementary models. She will also undertake a suite of training to support her professional development. The execution of this proposal will equip the candidate with a formidable skillset and a robust platform to launch her independent research program.

项目摘要：意义：我们经常因受伤，感染和疾病而损害。许多器官人体可以进行自我修复以在伤害后恢复其功能。这项恢复已完成通过成年干细胞的作用，该干细胞产生了潜水员类型的新细胞以取代受损材料。成年干细胞修复组织的能力使它们成为发展的目标恢复受伤或衰老受损的组织健康的疗法。但是，剩下很多关于干细胞后代如何采用适当的细胞命运来重塑组织的未知。这条路通往独立奖提案旨在了解产生特定细胞类型的机制再生哺乳动物组织。候选人与环境：获得独立途径奖的候选人Kara McKinley博士是致力于领导一个独立的研究小组在细胞生物学和再生医学的界面上。麦金莱博士在麻省理工学院的Iain Cheeseman博士实验室接受了细胞生物学和生物化学的培训。她发现了组装和调节细胞分裂机械所需的机制。在她期间在著名的细胞生物学家罗恩·维尔（Ron Vale）实验室的UCSF的博士后研究，她已经开发了类器官的长期实时成像的方法，它们是模仿的“迷你器官”培养系统人体外部器官的细胞组成，结构和反应。如本提议中所述，她将采用她的类器官成像方法，并结合定义信号的有针对性应用，了解外部线索如何改变两个高度再生时机中的细胞身份：小肠（AIM 1），和子宫内膜（子宫内膜； AIM 2）。职业发展：在陈述期间，候选人将获得鼠标遗传学的额外培训将她的发现从体外器官系统转化为体内环境，并在生殖生物学中转化为将她的方法从小肠癌转化为子宫内膜器官。结合研究小肠和子宫内膜为她的独立团体提供了一个独特而强大的平台揭示再生统一特征的常见工具和方法，并确定器官特异性生理学。候选人将与小鼠遗传学和复制生物学专家合作 UCSF建立必要的科学技能，以在这两个完整的模型中推动她的研究。她会的还接受一套培训以支持她的专业发展。该提案的执行将为候选人配备强大的技能和强大的平台，以启动其独立研究计划。