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.

项目概要：意义：我们的组织经常因受伤、感染和疾病而受到损害。人体受到损伤后，可以进行自我修复，恢复其功能，从而完成恢复。通过成体干细胞的作用，产生不同类型的新细胞来替代受损的物质。成体干细胞修复组织的能力使其成为开发细胞的有吸引力的目标恢复因损伤或衰老而受损的组织健康的疗法然而，还有很多工作要做。目前尚不清楚干细胞后代如何采用适当的细胞命运来重新填充组织。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。候选人和环境：独立之路奖的候选人卡拉·麦金利博士是致力于领导细胞生物学和再生医学交叉领域的独立研究小组。麦金利博士在麻省理工学院 Iain Cheeseman 博士的实验室接受了细胞生物学和生物化学方面的培训，她发现了组装和调节细胞分裂机器所需的机制。她在加州大学旧金山分校著名细胞生物学家 Ron Vale 博士的实验室进行博士后研究，开发了类器官的长期实时成像方法，类器官是模仿如本提案所述，体外器官的细胞组成、结构和反应。她将应用她的类器官成像方法，结合定义信号的有针对性的应用，了解外在线索如何改变两种高度再生组织中的细胞身份：小肠（目标 1），和子宫内膜（子宫内膜；目标 2）。职业发展：在指导期间，候选人将获得小鼠遗传学方面的额外培训将她从体外类器官系统的发现转化为体内环境，并在生殖生物学中转化为将她的方法从小肠类器官转化为子宫内膜类器官的组合研究。小肠和子宫内膜为她的独立团队提供了一个独特而强大的应用平台揭示再生的统一特征以及确定再生的关键方面的通用工具和方法候选人将与小鼠遗传学和生殖生物学专家合作。加州大学旧金山分校培养必要的科学技能来推动她在这两个互补模型中的研究。还将接受一系列培训以支持她的专业发展。为候选人提供强大的技能和强大的平台来启动她的独立研究项目。