Project title
製作並分析腎臟專一XBP-1剔除小鼠以了解XBP-1相關適應性未折疊蛋白在腎臟發育及損傷之角色
Internal ID
NSC101-2314-B002-150-MY3
Principal Investigator
Start Date
August 1, 2012
End Date
July 31, 2013
Investigators
Organizations
Partner Organizations
Develop and Analyze Kidney Specific Conditional XBP1 Knockout Mice to Investigate the Roles of XBP1-Related Adaptive Unfolded Protein Responses in Kidney Development and Injury = 製作並分析腎臟專一XBP-1剔除小鼠以了解XBP-1相關適應性未折疊蛋白在腎臟發育及損傷之角色
Description
Different physiological and pathological perturbations interfere with protein folding processes in the endoplasmic reticulum (ER) lumen, leading to accumulation of unfolded or misfolded proteins, a cellular condition termed “ER stress.” Protein folding stress triggers the activation of an adaptive reaction to cope with ER stress termed the unfolded protein response (UPR). Splicing X-Box binding protein-1 (sXBP-1) catalyzes the unconventional processing of the mRNA, plays the central roles to activate the UPRs. It controls the upregulation of a general pool of UPR-related genes involved in different processes including (a) Metabolic and redox, (b) Apoptosis, (c) Autophagy, (d) ER-associated degradation (ERAD), (e) chaperones and foldases and (f) vesicle traffickling. There is growing biomedical interest in investigating the regulatory mechanisms underlying UPR signaling and the development of strategies to target this pathway, since there is substantial evidence for the involvement of chronic ER stress in many diseases, including neurodegeneration, diverse forms of cancer, diabetes, and proinflammatory conditions. Regardless of etiology, all patients with chronic renal disease show a progressive decline in renal function with time. Chronic inflammation and diabetes are associated with renal fibrosis, so-called scarring, is a key factor of this pathophysiologic changes. Fibrosis involves an excess accumulation of extracellular matrix and usually results in loss of function when normal tissue is replaced with scar tissue. Before the development of chronic fibrosis, renal parenchyma attempts to maintain the integrity of tubules, there is an activation of proliferative pathways within the epithelial cells. If the proliferative forces or homeostatic factors within the kidney dissipate, the apoptotic pathway(s) overwhelms the ability of tubular epithelial cells to survive and tubular atrophy ensues. Our recent publication demonstrated the downregulation of adaptive UPRs and upregulation of overwhelming ER stess in the unilateral ureteral obstruction fibrosis model. Adequate UPRs might contribute to the restoration of renal insult, thus we believe that IRE1-XBP1 pathway plays a significant role in overcoming the kidney insult. However, XBP-1 deficiency leads to embryonic lethality due to impairment of liver function. To bypass this lethality, we need to design experiments by using a conditional KO allele of XBP-1 mice. It is deserved to explore the mechanisms of XBP-1-related signals in renal fibrosis and inflammation. We hope to achieve these goals within 3 years. In the first year, we will generate Kidney Tubular-Specific XBP-1 KO Mice, and then arrange functional analysis. In the second year, we will generation of Kidney Podocyte-Specific XBP-1 KO mice, and them arrange functional analysis. In the third year, we will explore the roles of Kidney-Specific XBP-1 in chronic tubulointerstitial fibrosis and diabetic glomerulosclerosis models. Using these available tools will help us to identify the physiological and pathological roles of adaptive UPR (splicing XBP-1) in the renal tubular and glomerular disease. We will get chances and comprehensive experiences in handling the transgenic and knockout mice. We hope such novel approaches can actively contribute to the National Research Program for Biopharmaceuticals (NRPB) in Taiwan.