SUBSTANCE P AND THE PATHOGENESIS OF CRYPTOSPORIDIOSIS IN AIDS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 隐孢子虫病，由原生动物寄生虫隐孢子虫引起，在免疫功能正常的宿主中引起自限性腹泻，在艾滋病患者中引起严重危及生命的腹泻。高效抗逆转录病毒疗法已被用于有效地治疗隐孢子虫病的一些，但不是所有的艾滋病患者。因此，迫切需要创新药物来治疗这种疾病。隐孢子虫感染导致肠道病理生理变化，如葡萄糖吸收不良、氯离子（Cl（-））分泌增加和上皮屏障破坏，导致疾病发病机制。为了开发对抗这种机会致病菌的工具，了解参与疾病发病机制的介质至关重要。P物质（SP）是一种神经肽和疼痛递质，位于胃肠道。SP可引起人胃肠道组织Cl（-）分泌。然而，其在隐孢子虫病中的作用尚未得到充分研究。用逆转录-PCR、免疫组化和酶联免疫吸附试验分别检测了隐孢子虫感染前后猕猴空肠SP和SP受体mRNA和蛋白水平。利用感染C.通过Ussing chamber技术对parvum进行鉴定。空肠SP和SP受体mRNA和蛋白表达水平在C.并伴有基础离子分泌增加和葡萄糖吸收不良。用SP受体拮抗剂阿瑞匹坦（Emend; Merck，怀特豪斯站，NJ）体外处理从感染的猕猴获得的样品完全逆转了基础离子分泌的增加并纠正了葡萄糖吸收不良。我们的研究结果提高了使用SP受体拮抗剂治疗隐孢子虫病相关症状的可能性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cryptosporidiosis, caused by the protozoan parasite Cryptosporidium, causes self-limited diarrhea in immunocompetent hosts and severe life-threatening diarrhea in AIDS patients. Highly active antiretroviral therapy has been used to effectively treat cryptosporiosis in some but not all AIDS patients. Therefore, there is an urgent need for innovative drugs to treat this disease. Cryptosporidium infection results in intestinal pathophysiological changes such as glucose malabsorption, increased chloride ion (Cl(-)) secretion, and epithelial barrier disruption, leading to disease pathogenesis. In order to develop tools to combat this opportunistic pathogen, it is vital to understand mediators involved in disease pathogenesis. Substance P (SP), a neuropeptide and pain transmitter, is located in the gastrointestinal tract. SP can cause Cl(-) secretion in human gastrointestinal explants. However, its role in cryptosporidiosis has not been fully studied. Jejunal samples from macaques before and after Cryptosporidium parvum infection were assayed for SP and SP receptor mRNA and protein levels by reverse transcription-PCR and by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. The role of SP in pathophysiological alterations, such as Cl(-) secretion and glucose malabsorption, was studied using tissues derived from macaques infected with C. parvum by the Ussing chamber technique. SP and SP receptor mRNA and protein expression levels were increased in jejunal samples following C. parvum infection and were accompanied by increased basal ion secretion and glucose malabsorption. In vitro treatment of samples obtained from infected macaques with the SP receptor antagonist aprepitant (Emend; Merck, Whitehouse Station, NJ) completely reversed the increase in basal ion secretion and corrected the glucose malabsorption. Our findings raise the possibility of using SP receptor antagonists for the treatment of symptoms associated with cryptosporidiosis.