Congenital, chronic and acute kidney diseases cause significant morbidity, mortality and economic burden to our society. A significant impact in all these areas will be made by identifying pathogenetic mechanisms that cause kidney diseases. Because humans and mice share a number of characteristics of kidney development and function, and animal models of renal injury recapitulate events that are similar to humans, genetically engineered mouse models offer an important tool to delineate molecular mechanisms of renal diseases. A prevailing idea is that a number of these conditions are caused by aberrant function of genes that are also important in early kidney formation. Because absence of these genes from the beginning of kidney development often results in renal or other abnormalities and lethality, there is scarcity of animal models to examine the role of these genes in kidney disease in adulthood. Glial cell line-derived neurotrophic factor (GDNF), its coreceptor Gfra1 and receptor Ret constitute a signaling system that is critical for kidney development. It also regulates function of several tissue specific progenitors and is implicated in repair, regeneration and therapy of a number of conditions. However, biological roles of this signaling system in the postnatal kidney in normal and abnormal conditions are not known since its absence results in renal agenesis and lethality. We hypothesize that GDNF-Gfra1-Ret signaling is required for kidney maintenance in adult mice, it is important in kidney protection and regeneration after acute kidney injury (AKI), and GDNF can protect kidneys from AKI due to different types of insults by acting through Gfra1-Ret pathway. We have generated a number of animal models that are necessary to test these hypotheses. For example, to overcome lethality we have developed unique mouse models that will inactivate Gfra1 or Ret signaling after initial kidney development (conditional mice). To identify Gfra1 or Ret expressing cells in normal and disease states, we have generated """"""""reporter"""""""" mice. To determine therapeutic potential of GDNF, we have established systemic delivery method that has shown protection in ischemic-reperfusion injury to the brain. The objective of specific Aim 1 in this proposal will be to use GDNF, Gfra1 and Ret reporter mice to identify where these proteins are expressed in the normal postnatal kidney and how their expression changes during AKI particularly in relation to repair and regeneration.
In Specific Aim 2 we will use Gfra1 and Ret conditional mice to determine the impact of their loss on normal renal function in adult mice, and in AKI.
In Aim 3, we will determine if exogenous treatment with GFLs in different AKI models is renoprotective, stimulates regeneration and occurs through Gfra1. Through these studies we will determine the importance of this pathway in renal health and disease. The insights gleaned will be of interest to a broad group of basic scientist, clinicians and patients affected by renal diseases.
GDNF-Gfra1-Ret signaling pathway is critical for kidney development and regulates function of a number of tissue specific stem cells. In this proposal we will utilize novel animal models to modulate this pathway and determine its role in the function of postnatal kidney in normal and disease states and examine if treatment with GDNF can protect kidneys from renal failure. The studies will provide novel insights into mechanisms of repair and regeneration and therapy in injured kidneys.
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