一、选题依据、目的和意义：
Cystinuria is an autosomal recessive disorder caused by mutations in gene SLC3A1 on chromosome 2 or an incompletely dominant disorder caused by mutations in gene SLC7A9 on chromosome 19. Each gene codes for a component of the major proximal renal tubular cystine and dibasic amino acid transporter. These mutations result in abnormal reabsorption of L-cystine and dibasic amino acids from the luminal fluid of the renal proximal tubule, leading to elevated concentrations of these amino acids in the urine of affected individuals. Defective expression in the small bowel leads to reduced absorption of these amino acids from the intestinal lumen. Because of its limited aqueous solubility, L-cystine crystallizes readily in urine and forms L-cystine stones in the kidney, ureter, and bladder. Although the incidence of L-cystine stones is much lower than that of calcium oxalate stones, L-cystine stones are larger, occur at a young age, recur more frequently, and are more likely to cause chronic kidney disease. Cystine stones account for 1% of all stones and as many as 7% of stones in children. Cystinuria is a chronic, lifelong condition, and patients with cystinuria have a gt;50% chance of stone formation during their lifetime, most experiencing onset and diagnosis between the ages of 2 and 40.
二、本课题目前国内外研究的动态、水平
Current clinical treatment of cystinuria has not changed over the last 30 years and is aimed at reducing the concentration of free L-cystine in urine and increasing its solubility. A high fluid intake of around 4minus;5 L a day and alkalinization of urine pH with citrate or bicarbonate salt can suppress but may not completely prevent stone formation. Drug therapy, based on disulfide exchange with D-penicillamine or alpha;-mercaptopropionylglycine with L-cystine to generate more soluble mixed disulfides, has been used for severe cases. These drugs, however, have side elects that include loss of taste, fever, proteinuria, serum sickness-type reactions, and even frank nephritic syndrome.
Recently, Ward and his co-workers reported an alternative approach to prevent cystinuria based on crystal growth inhibition, which is achieved through the binding of tailored crystal growth inhibitors (aka molecular imposters), L-cystine dimethyl ester (CDME) and L-cystine methyl ester (CME), to L-cystine crystal surfaces. Real-time in situ atomic force microscopy (AFM) revealed that CDME and CME dramatically reduce the growth velocity of six symmetry-equivalent{100} steps because of specific binding to crystal growth sites, which frustrates the further attachment of L-cystine molecules. CDME was found to significantly reduce stone burden in cystinuria mice compared with a water-treated group accompanied by the formation of smaller stones, but did not prevent stone formation. We report the discovery of two novel L-cystine diamides, L-cystine bismorpholide (CDMOR, 1a) and L-cystine bis(N′-methylpiperazide) (CDNMP, 1b), which are more elective inhibitors of L-cystine crystallization and exhibit significantly better stability.
三、课题研究的主要内容
四、本课题特色、预期取得的结果
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