Investigating the principles of physiological and pathological vascular remodeling via 4D imaging of live mouse skin

通过活体小鼠皮肤 4D 成像研究生理和病理血管重塑的原理

• 批准号: 10739431
• 负责人: Chen Yuan Kam
• 金额: $ 10.6万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739431
• 关键词: 4D Imaging; Ablation; Address; Adult; Age; Architecture; Behavior; Birth; Blood Vessels; Blood flow; Cells; Cellular Morphology; Characteristics; Coupling; Cutaneous; Data; Development; Endothelial Cells; Endothelium; Epidermis; Genetic; Health; Homeostasis; Human; Image; Imaging Techniques; Imaging technology; Injectable; Injury; Kinetics; Lasers; Maintenance; Mediating; Membrane; Modeling; Molecular; Monitor; Morphology; Mus; Mutant Strains Mice; Natural regeneration; Neonatal; Nutrient; Organ; Pathologic; Pathology; Physiological; Play; Process; Property; Regenerative capacity; Regulation; Reporter; Research; Resolution; Role; Signal Transduction; Skin; Skin repair; Solid; Structure; Techniques; Technology; Temperature; Testing; Time; Tissues; VEGFA gene; Vascular Permeabilities; Vascular regeneration; Vascular remodeling; Vascularization; Visualization; cell behavior; cell motility; cell type; experimental study; hemodynamics; imaging approach; improved; in vivo; infancy; injury and repair; innovation; intravital imaging; migration; mouse model; multiphoton microscopy; mutant; neonate; network architecture; programs; regenerative; repaired; response; spatiotemporal; time use; tissue oxygenation; tool; transcriptomics; vascular abnormality; vessel regression; wound; wound healing; wound vascularization

PROJECT SUMMARY The cutaneous vasculature is a crucial yet understudied component of the skin, responsible for essential functions such as tissue oxygenation, exchange of nutrients and soluble factors, and temperature control. While we have a significant understanding of vascular abnormalities present in various skin pathologies, we lack an understanding of both physiological remodeling and homeostatic mechanisms sustaining lifelong function. Specifically, we lack the resolution of the coordinated cellular behaviors that drive developmental vascular remodeling, as well as those that underlie vascular regeneration in the face of injury, particularly in the context of hemodynamic status. I hypothesize that network-wide coordination of EC behaviors in relation to hemodynamic changes regulates developmental and regenerative remodeling programs of the skin vasculature. To test this hypothesis, I have established an intravital imaging technique that allows for the longitudinal tracking and manipulation of the endothelial cells (ECs) that constitute the lining of all blood vessels in the skin of a live mouse. In Aim 1, I will investigate the neonatal vessel remodeling program and underlying EC behaviors that orchestrate the establishment of skin vascular network architecture and blood flow efficiency. Following establishment of adult vascular homeostasis, I will probe the cellular mechanisms that regulate the maintenance of adult vessel integrity via a targeted laser ablation approach, modeling the discrete membrane damage inflicted upon the endothelium due to shear and contractile forces. My preliminary data shows that EC migration within existing vessel structures is a critical EC behavior that underlies network-wide vessel regression during neonatal remodeling, as well as the reparative response of adult ECs to local damage. In Aim 2, I will transition my studies towards the understanding of the skin vasculature in the context of pathological states. Firstly, I will investigate the wound vascularization mechanisms of neonatal versus adult skin, and delineate the differential remodeling properties that enable the enhanced wound revascularization in neonatal skin that we have observed in preliminary experiments. Second, I will determine how coordination of flow-dependent EC rearrangement impacts the ability of adult wounds to revascularize via a genetic mutant model that uncouples the ability of ECs to polarize with respect to blood flow direction. To achieve these aims, I will use an integrated approach of cutting-edge imaging technology, transcriptomics, and genetic mouse models. This research is significant because we expect to uncover global cellular and molecular mechanisms that coordinate vascular development, homeostasis, and injury repair. My findings will likely drive innovation in related fields, given the ubiquity and crucial roles of the vasculature in all organs.

项目总结 皮肤血管是皮肤的一个重要组成部分，但尚未得到充分的研究，它负责 具有组织氧合、营养物质和可溶性因子的交换、温度控制等功能。 虽然我们对各种皮肤病理中存在的血管异常有很大的了解，但我们 缺乏对维持终生的生理重构和动态平衡机制的了解 功能。具体地说，我们缺乏对推动发育的协调细胞行为的解析 血管重塑，以及那些在面对损伤时，尤其是在 血流动力学状态的背景。我假设电子商务行为在网络范围内的协调 血液动力学变化调节皮肤的发育和再生重塑程序 脉管系统。为了验证这一假设，我建立了一种活体成像技术，允许 对构成所有血液衬里的内皮细胞(ECs)的纵向跟踪和操纵 活老鼠皮肤上的血管。 在目标1中，我将研究新生儿血管重塑计划和潜在的EC行为， 协调建立皮肤血管网络架构和血液流动效率。跟随 成人血管动态平衡的建立，我将探索调节 通过靶向激光消融方法维持成人血管的完整性，模拟离散的膜 由于剪切力和收缩力对内皮造成的损伤。我的初步数据显示欧共体 现有血管结构内的迁移是网络范围内血管的关键EC行为 在新生儿重塑过程中的退化，以及成年内皮细胞对局部损伤的修复反应。在……里面 目标2，我将把我的研究转移到对皮肤血管系统的理解上 病态。首先，我将研究新生儿和成人伤口血管形成的机制。 皮肤，并描绘了不同的重塑属性，使增强伤口血运重建在 我们在初步实验中观察到的新生儿皮肤。第二，我将确定如何协调 依赖流动的EC重排影响成人伤口通过基因突变重新血运重建的能力 分离内皮细胞相对于血流方向极化的能力的模型。为了实现这些目标， 我将使用尖端成像技术、转录学和遗传老鼠的综合方法 模特们。这项研究意义重大，因为我们希望揭示全球细胞和分子机制 协调血管发育、动态平衡和损伤修复。我的发现可能会推动 相关领域，鉴于血管系统在所有器官中的普遍存在和关键作用。