Zebrafish model of acute kidney injury

斑马鱼急性肾损伤模型

• 批准号: 8656202
• 负责人: Aleksandr Vasilyev
• 金额: $ 7.91万
• 依托单位: NEW YORK INST OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656202
• 关键词: Ablation; Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Biomechanics; Blood Vessels; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chemicals; Commit; Dialysis procedure; Distal; Duct (organ) structure; Epithelial; Epithelial Cells; Epithelium; Event; Fishes; Fluorescent Antibody Technique; Fluorescent in Situ Hybridization; Health Resources; Hospitalization; Hour; Imagery; In Situ; Injury; Kidney; Label; Lead; Length of Stay; Link; Location; Mechanics; Mediating; Medical; Metaplasia; Metaplastic; Modeling; Molecular; Natural regeneration; Nephrons; PIK3CG gene; Patients; Pattern; Play; Process; Public Health; Recovery; Renal tubule structure; Research; Risk; Role; Secondary to; Series; Signal Transduction; Societies; Staging; Stretching; System; Testing; Time; Tissues; Transgenic Organisms; Tretinoin; Zebrafish; cell behavior; cell motility; cell type; cost; design; kidney repair; migration; morphogens; mortality; nephrogenesis; novel; programs; regenerative; repaired; research study; response; response to injury; treatment strategy

Summary Acute kidney injury is a common medical problem with a significant impact on society. It results in the increased risk of death, lengthening of hospital stay and increased cost of hospitalization. Kidney has a remarkable capacity to regenerate but despite this potential for regeneration, the mortality rate for the AKI patients who require dialysis is still 50%-80%. Thus, there remains a need to develop medical approaches that would enhance the intrinsic ability of the kidney tissue to regenerate. Utilizing these intrinsic mechanisms of kidney regeneration will help to design optimal strategies for the treatment of patients with AKI. In order to develop such strategies, it is critical to understand the mechanisms by which kidney recovers from injury. It has been recently shown that epithelial repair, albeit influenced by stromal, vascular and circulating factors, is a process intrinsic to the kidney epithelium. Therefore, identifying the basic mechanisms governing the intrinsic epithelial restitution is central to the understanding of how kidney recovers from AKI. It has been long acknowledged that cell proliferation, cell de-differentiation and perhaps cell migration may play a significant role in epithelial restitution. Unfortunately, traditional mammalian models of AKI do not allow for a sufficient spatio-temporal control to investigate the precise role these processes play in kidney repair. Thus, we developed a novel zebrafish model of AKI that overcomes the limitations of mammalian systems. Using this model, we discovered that collective cell migration is an early response of surviving epithelium to acute injury that precedes the cell proliferative response by at least several hours. This is a novel finding that places collective cell migration at the center of kidney repair. Furthermore, we found that during kidney development collective epithelial migration stimulates epithelial proliferation secondary to cell stretch induced by this collective migration. The same components are present during kidney repair - cell migration, subsequent cell stretch, and a delayed onset of cell proliferation. The proposed study involves a series of experiments that will investigate whether this biomechanical link is a primary determinant of cell proliferative response in regenerating kidney epithelia. We will also test the role of Pi3K signaling in mediating the proliferative response. In addition, we will investigate the degree of epithelial plasticity during kidney repair by combining our injury model with a chemical treatment of the regenerating zebrafish. Overall, these studies will advance our understanding of the interplay between basic cellular processes of migration, proliferation, de-differentiation and metaplasia as they apply to kidney repair after acute injury. They will set the stage for designing targeted therapies addressing various components of kidney repair.

总结 急性肾损伤是一种常见的医学问题，对社会有着重大的影响。其导致 死亡风险增加、住院时间延长和住院费用增加。肾脏有一个 尽管有这种再生的潜力， 需要透析的阿基患者仍占50%-80%。因此，仍然需要开发医疗器械。 增强肾脏组织再生的内在能力的方法。利用这些 肾脏再生的内在机制将有助于设计治疗 阿基患者。为了制定这样的战略，关键是要了解的机制， 哪一个肾能从损伤中恢复最近的研究表明，上皮修复，尽管受到 基质、血管和循环因子是肾上皮固有的过程。因此，我们认为， 确定支配内在上皮恢复的基本机制是 了解肾脏如何从阿基中恢复。长期以来人们一直认为细胞增殖， 细胞去分化和可能的细胞迁移可能在上皮恢复中起重要作用。 不幸的是，阿基的传统哺乳动物模型不允许充分的时空控制 以研究这些过程在肾脏修复中的确切作用。因此，我们开发了一种新的 阿基的斑马鱼模型，克服了哺乳动物系统的局限性。使用该模型，我们 发现集体细胞迁移是存活上皮对急性损伤的早期反应， 在细胞增殖反应之前至少几个小时。这是一个新奇的发现， 肾脏修复中心的集体细胞迁移。此外，我们发现，在肾脏 发育集体上皮迁移刺激继发于细胞牵张的上皮增殖 这一集体迁徙的结果。在肾脏修复过程中存在相同的成分-细胞 迁移、随后的细胞伸展和细胞增殖的延迟发生。拟定研究 涉及一系列的实验，将调查这种生物力学联系是否是主要的 再生肾上皮细胞增殖反应的决定因素。我们还将测试 Pi 3 K信号转导介导增殖反应。此外，我们还将调查 通过结合我们的损伤模型和化学治疗， 再生斑马鱼。总的来说，这些研究将促进我们对 迁移、增殖、去分化和化生的基本细胞过程， 急性损伤后的肾脏修复他们将为设计靶向治疗奠定基础， 肾脏修复的各种组成部分。