Mechanisms modulating cell identity in regenerative mammalian epithelia

项目概要： 意义：我们的组织经常受到伤害，感染和疾病的损害。许多器官在 人体在受到损伤后可以进行自我修复，以恢复其功能。这一恢复已完成 通过成体干细胞的作用，产生不同类型的新细胞来取代受损的物质。 成体干细胞修复组织的能力使其成为开发干细胞的一个有吸引力的目标。 用于恢复因损伤或老化而受损的组织的健康的疗法。然而， 干细胞后代如何采用适当的细胞命运来重新填充组织尚不清楚。这条通往 独立奖的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：这一独立之路奖的候选人，卡拉麦金利博士，是 致力于在细胞生物学和再生医学的接口领导一个独立的研究小组。 博士麦金利在麻省理工学院的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， 她发现了细胞分裂机器的组装和调节所需的机制。期间 她在加州大学旧金山分校著名细胞生物学家罗恩瓦尔博士的实验室进行博士后研究， 用于类器官的长期活体成像的方法，这是模拟器官的“微型器官”培养系统。 细胞组成、结构和体外器官的反应。如本提案所述， 她将应用她的类器官成像方法，结合有针对性地应用定义的信号， 了解外在线索如何改变两个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 将她的发现从体外类器官系统转化为体内环境，并在生殖生物学中， 将她的方法从小肠类器官转化为子宫内膜类器官。综合研究， 小肠和子宫内膜为她的独立小组提供了一个独特而强大的平台， 共同的工具和方法，以揭示再生的统一特征，以及确定的关键方面， 器官特异性生理学候选人将与小鼠遗传学和生殖生物学专家在 加州大学旧金山分校建立必要的科学技能，以推动她在这两个互补模型的研究。她将 她还参加了一系列培训，以支持她的专业发展。本提案的执行将 为候选人提供强大的技能和强大的平台，以启动她的独立研究计划。

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.