Zebrafish model of acute kidney injury

斑马鱼急性肾损伤模型

• 批准号: 8610300
• 负责人: Aleksandr Vasilyev
• 金额: $ 7.2万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610300
• 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; public health relevance; regenerative; repaired; research study; response; response to injury; treatment strategy

DESCRIPTION (provided by applicant): 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 intrinic 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 a 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 th 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.

描述（由申请人提供）：急性肾损伤是一种常见的医学问题，对社会有重大影响。它导致死亡风险增加、住院时间延长和住院费用增加。肾脏具有非凡的再生能力，但尽管有这种再生潜力， 需要透析的仍占50%-80%。因此，仍然需要开发将增强肾组织再生的内在能力的医学方法。利用肾再生的这些内在机制将有助于设计治疗阿基患者的最佳策略。为了制定这样的战略，关键是要了解这些机制 肾脏从损伤中恢复。最近的研究表明，上皮修复，虽然受到基质，血管和循环因素的影响，是一个内在的过程，肾脏上皮。因此，确定支配内在上皮恢复的基本机制对于理解肾脏如何从阿基中恢复至关重要。长期以来，人们一直认为细胞增殖、细胞去分化和细胞迁移可能在细胞凋亡中起作用。 在上皮修复中的重要作用。不幸的是，阿基的传统哺乳动物模型不允许足够的时空控制来研究这些过程在肾修复中发挥的确切作用。因此，我们开发了一种新的阿基斑马鱼模型，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，其先于细胞增殖反应至少几个小时。这是一个新的发现，将集体细胞迁移置于肾脏修复的中心。此外，我们发现，在肾脏发育过程中，集体上皮迁移刺激上皮细胞增殖继发于细胞拉伸诱导的这种集体迁移。在肾修复过程中也存在相同的成分-细胞迁移，随后的细胞伸展和细胞增殖的延迟发生。这项研究涉及一系列实验，将调查这种生物力学联系是否是再生肾上皮细胞增殖反应的主要决定因素。我们还将测试Pi 3 K信号传导在介导增殖反应中的作用。此外，我们将通过将我们的损伤模型与再生斑马鱼的化学处理相结合来研究肾修复过程中上皮可塑性的程度。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之间的相互作用的理解，因为它们适用于急性损伤后的肾修复。他们将为设计针对肾脏修复各个组成部分的靶向治疗奠定基础。