The roles of cell death and mechanical signaling in aging intestinal stem cells

细胞死亡和机械信号在衰老肠道干细胞中的作用

• 批准号: 10371731
• 负责人: David Castillo-Azofeifa
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2022-04-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371731
• 关键词: Affect; Age; Aging; Apoptosis; Atomic Force Microscopy; Award; Biochemical; Biology of Aging; Calcium Signaling; Cell Communication; Cell Compartmentation; Cell Death; Cell Death Signaling Process; Cell Differentiation process; Cell Proliferation; Cells; Cellular biology; Cessation of life; Colorado; Constipation; Cues; Data; Development; Elderly; Environment; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Equilibrium; Event; Feedback; Foundations; Frequencies; Gastrointestinal tract structure; Gene Expression Profile; Genetic; Goals; Health; Homeostasis; Human; Hypersensitivity; Imaging Device; Impairment; In Vitro; Incidence; Incontinence; Inflammation; Injections; Intestinal Diseases; Intestines; Ion Channel; Laboratories; Lead; Life; Malabsorption Syndromes; Malignant Neoplasms; Mechanics; Medical; Mentors; Modeling; Molecular; Movement; Mus; Natural regeneration; Nutrient; Older Population; Organ; Organoids; Output; Partner in relationship; Pathway interactions; Phase; Physiology; Play; Population; Quality of life; Regenerative Medicine; Research; Research Institute; Role; Signal Transduction; Small Intestines; Stem Cell Development; Structure; System; Techniques; Testing; Therapeutic; Tissues; Tongue; Training; Training Programs; Universities; Villus; Work; age related; aged; career; career development; cell age; crypt cell; desensitization; design; epithelium regeneration; experience; experimental study; gastrointestinal; gut health; improved; in vivo; intestinal crypt; intestinal epithelium; loss of function; mechanical force; mechanical signal; mechanical stimulus; mechanotransduction; mortality; nutrient absorption; organ injury; organ regeneration; pathogen; platform-independent; programs; response; self renewing cell; self-renewal; single cell sequencing; single-cell RNA sequencing; skills; stem cell differentiation; stem cell function; stem cell proliferation; stem cell self renewal; stem cells; tissue stem cells; tool; transcriptomics

PROJECT SUMMARY: Significance: Our tissues are comprised of populations of cells that are constantly interacting. One such cellular interaction crucial for tissue health is the balance between stem cell proliferation and differentiated cell death, while imbalance of these events can lead to overproduction of cells and cancer or loss of tissue integrity. During aging, there is a progressive decline in the ability of tissues to maintain homeostasis and regenerate due to impaired cell interactions. How the equilibrium between stem cells and mature cells changes during aging is not well understood. Moreover, much remains unknown about the signals that establish the feedback between stem cells and differentiated cells. This Pathway to Independence Award proposal seeks to understand the biochemical and mechanical stimuli that regulate the balance of stem cells and cell death, and how they are affected during aging. Candidate and environment: The candidate for this Pathway to Independence Award, Dr. David Castillo- Azofeifa, is committed to leading an independent research group at the interface of aging, cell biology, and regenerative medicine. Dr. Castillo-Azofeifa was trained in cell biology, stem cells and development in the laboratory of Dr. Linda Barlow at University of Colorado Anschutz Medical Campus, where he uncovered mechanisms required for tongue epithelium regeneration. During his postdoctoral studies at UCSF in the laboratory of stem cell and developmental biologist Dr. Ophir Klein, he has developed genetic and imaging tools, while using the intestine as a system to study aging. As described in this proposal, he will apply his in vivo and in vitro tools to understand how molecular (Aim 1) and mechanical (Aim 2) cues regulate intestinal stem cells during aging. Career development: During the mentored period, the candidate will gain training in new techniques, including single-cell RNA sequencing, microdroplet injection, atomic force microscopy, and micropipette pulling. The candidate will work with experts in aging biology at UCSF and the Buck Institute for Research on Aging to build the necessary scientific skills to propel his research in this field. He will also undertake a program of training to support his professional development. Combining studies of biochemical signaling and mechanobiology in aging presents a unique and powerful platform for his independent group to apply common tools and approaches to reveal unifying features of regeneration, as well as to identify key aspects of age-specific physiology. The execution of this proposal will equip the candidate with a formidable skillset and a robust platform to launch his independent research career.

项目概要： 意义：我们的组织由不断相互作用的细胞群组成。一个这样的细胞 对组织健康至关重要的相互作用是干细胞增殖和分化的细胞死亡之间的平衡， 而这些事件的不平衡可导致细胞的过度产生和癌症或组织完整性的丧失。期间 随着年龄的增长，组织维持体内平衡和再生的能力逐渐下降， 细胞相互作用受损。衰老过程中干细胞和成熟细胞之间的平衡如何变化， 很好理解。此外，关于建立茎与茎之间反馈的信号， 细胞和分化细胞。这条独立之路奖提案旨在了解 调节干细胞和细胞死亡的平衡的生物化学和机械刺激，以及它们是如何 在衰老过程中受到影响。 候选人和环境：这条独立之路奖的候选人，大卫卡斯蒂略博士- Azofeifa致力于领导一个独立的研究小组，研究衰老、细胞生物学和 再生医学Castillo-Azofeifa博士曾在法国巴黎大学接受细胞生物学、干细胞和发育方面的培训， 在科罗拉多大学安舒茨医学院的琳达巴洛博士的实验室里， 舌上皮再生所需的机制。在加州大学旧金山分校的博士后研究期间， 在干细胞和发育生物学家Ophir Klein博士的实验室，他开发了遗传和成像工具， 同时利用肠道作为一个系统来研究衰老。如本建议书所述，他将在体内和 了解分子（目标1）和机械（目标2）线索如何调节肠干细胞的体外工具 在老化过程中。 职业发展：在指导期间，候选人将获得新技术的培训，包括 单细胞RNA测序、微滴注射、原子力显微镜和微量移液管拉动。的 候选人将与加州大学旧金山分校和巴克老龄研究所的衰老生物学专家合作， 必要的科学技能来推动他在这一领域的研究。他还将进行一项培训计划， 支持他的专业发展。衰老中生化信号传导和机械生物学的结合研究 为他的独立小组提供了一个独特而强大的平台，可以应用通用的工具和方法， 揭示再生的统一特征，以及确定特定年龄生理学的关键方面。的 执行这一建议将使候选人具备强大的技能和强大的平台，以启动他的 独立的研究生涯。