SUBSTANCE P AND THE PATHOGENESIS OF CRYPTOSPORIDIOSIS IN AIDS

P 物质与艾滋病隐孢子虫病的发病机制

• 批准号: 7349017
• 负责人: PREMA ROBINSON
• 金额: $ 6.54万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349017
• 关键词: SUBSTANCE; PATHOGENESIS; CRYPTOSPORIDIOSIS; AIDS

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 parvum causes self-limited diarrhea in AIDS patients. There is no specific prevention or therapy available for cryptosporidiosis. Therefore, there is an urgent need for innovative drugs to treat this disease. Cryptosporidium infection results in intestinal path physiologic changes such as glucose-malabsorption, increased chloride-ion (CI^-) 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 CI^- secretion in human gastrointestinal-explants. However, its role in cryptosporidiosis has not been fully studied. Jejunal samples from macaques before and after C. parvum infection were assayed for SP and SP receptor, NK1 (neurokinin 1) mRNA and protein levels by RT-PCR and by immunohistochemistry and ELISA, respectively. Path physiologic alterations, such as CI^- secretion and glucose-malabsorption and the role of SP in these alterations was also studied using tissues derived from macaques infected with C. parvum by the Ussing chamber technique. SP and NK1 mRNA and protein expression were increased in jejunal samples following C. parvum infection and were accompanied by increased CI^- secretion and glucose-malabsorption. In vitro treatment of samples obtained from infected macaques with SP receptor antagonist, Emend completely reversed the increase in CI^- secretion and corrected the glucose-malabsorption. Our findings raise the possibility of using SP receptor antagonists for treatment of syptoms associated with this disease.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。隐孢子虫病，由原生动物寄生虫微小隐孢子虫引起，导致艾滋病患者自限性腹泻。隐孢子虫病没有特异性的预防或治疗方法。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路径生理变化，例如葡萄糖吸收不良、氯离子（Cl-）分泌增加和上皮屏障破坏，从而导致疾病发病机制。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可以引起人胃肠道外植体中的C14-分泌。然而，其在隐孢子虫病中的作用尚未得到充分研究。在C.分别采用RT-PCR、免疫组织化学和ELISA法检测微小疟原虫感染后SP和SP受体、NK 1（神经激肽1）mRNA和蛋白水平。还使用来自感染C的猕猴的组织研究了路径生理学改变，例如Cl-2分泌和葡萄糖吸收不良以及SP在这些改变中的作用。通过Ussing chamber技术对parvum进行鉴定。空肠SP和NK 1 mRNA和蛋白表达均增加。小孢子虫感染，并伴有C1 - 6分泌增加和葡萄糖吸收不良。用SP受体拮抗剂Emend对从感染的猕猴获得的样品进行体外处理，完全逆转了Cl-2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受体拮抗剂治疗与这种疾病相关的症状的可能性。