Nanosystems with different biological properties and compositions have been extensively investigated for drug delivery applications. Nanoparticles (NPs) fabricated through various techniques have elevated therapeutic efficacy, provided stability to the drugs and proved capable of targeting the cells and controlled release inside the cell. Autophagy, a lysosomal degradation pathway that is essential for survival, differentiation, development, and homeostasis. Previous studies have demonstrated that autophagy was able to capture and degrade inflammasomes. Inflammasomes are a group of protein complexes that recognize a diverse set of inflammation-inducing stimuli. In a cohort of renal biopsies from patients with nondiabetic kidney disease, levels of NLRP3 inflammasome correlate with renal function, strongly suggesting that NLRP3 inflammasome contributes to the pathogenesis of chronic kidney disease. Resveratrol is one of the most biologically active polyphenols present in red wine and has been pharmacologically evaluated for a variety of illnesses. Resveratrol has low renal toxicity and is known to have beneficial effects in renal disease. However, resveratrol has low bioavailability. Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. MN has limited available treatments. Therefore, there is a need to conduct more trials to find the newer agents. Of note, the M-type phospholipase A2 receptor (PLA2R) was recently identified as the major target antigen in adult idiopathic MN, being circulating antibodies against PLA2R found in about 70% of the patients but only rarely in other glomerulonephritides. PLA2R are specific markers of idiopathic MN. In this project, we will utilize poly (lactic-coglycolic acid) (PLGA), iron oxide (Fe3O4) or gold (Au) for the synthesis of resveratrol of NPs conjugated with PLA2R RNA aptamer. Furthermore, we will examine the mechanism by which resveratrol NP modulates the regulation of inflammasome and autophagy in differentiated THP-1 cells (human monocytic cells differentiated to macrophages) and human kidney cell lines (HEK293 and HK-2 cells). We will test the effect of resveratrol NP conjugated with PLA2R RNA aptamer on a MN mice model. Here, we outline research goals that hope to achieve within three year. First year: We will synthesize the nanocarriers conjugated with PLA2R RNA aptamer. Furthermore, we will examine cytotoxicity and pharmacokinetics of these NPs in vivo. We will modify stable nanocarriers that provide cell targeting, drug storage and controlled drug release. To investigate the biodistribution of NPs, fluorescence-labeled NPs will be injected intravenously in mice. After multiple time intervals, the distribution of NPs will be visualized and quantified using the Xenogen IVIS. Second year: We will examine whether resveratrol NP induces autophagy in differentiated THP-1 cells and human kidney cell lines. The anti-inflammatory profiles of resveratrol NP on inflammasome and cytokine synthesis will be investigated. To understand the mechanism by which resveratrol NP modulates the regulation of inflammasome. Also, we will analyze whether resveratrol NP inhibits inflammasome through the induction of autophagy. Third year: To establish a MN mice model. We will confirm the pathologies characteristic of nephrotic syndromes in MN mice model. Furthermore, the effectiveness of resveratrol NP with PLA2R RNA aptamer will be investigated in MN mice model. We will analyze the relationship between inflammasome and autophagy in MN model. PLA2R targeted resveratrol NP may be potential tool in treating MN with respect to its anti- inflammasome and autophagic response.
|Effective start/end date||8/1/16 → 7/31/17|