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.
Acute kidney injury (AKI) is a serious medical problem that has a significant impact on patient mortality. The aim of this study is to use the strengths of zebrafish model to better understand cellular and molecular events underlying kidney repair after acute insult. The ultimate objective is to harness and aid the natural repair mechanisms in order to design optimal treatments for patient recovery after AKI. This research program has direct relevance to public health because AKI affects millions of people and places a substantial strain on public health resources.
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