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: 7562283
• 负责人: PREMA ROBINSON
• 金额: $ 7.16万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562283
• 关键词: Acquired Immunodeficiency Syndrome; Biological Assay; Chloride Ion; Computer Retrieval of Information on Scientific Projects Database; Cryptosporidiosis; Cryptosporidium; Cryptosporidium parvum; Diarrhea; Disease; Disruption; Enzyme-Linked Immunosorbent Assay; Epithelial; Funding; Gastrointestinal tract structure; Glucose; Grant; Highly Active Antiretroviral Therapy; Human; Immunocompetent; Immunohistochemistry; In Vitro; Infection; Institution; Intestines; Ions; Life; Macaca; Malabsorption Syndromes; Mediator of activation protein; Merck brand of aprepitant; Messenger RNA; Neuropeptides; Pain; Parasites; Pathogenesis; Patients; Pharmaceutical Preparations; Propionibacterium acnes; Proteins; Research; Research Personnel; Resources; Reverse Transcription; Role; Sampling; Source; Substance P; Substance P Receptor; Symptoms; Techniques; Therapeutic Corynebacterium Parvum; Tissues; United States National Institutes of Health; aprepitant; gastrointestinal; innovation; pathogen; protein expression; tool

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 隐孢子虫病由原生动物寄生虫隐孢子虫引起，可导致免疫功能正常的宿主出现自限性腹泻，并导致艾滋病患者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治疗一些但并非所有艾滋病患者的隐孢子虫病。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、上皮屏障破坏等，从而导致疾病发病。为了开发对抗这种机会性病原体的工具，了解疾病发病机制中涉及的介质至关重要。 P 物质 (SP) 是一种神经肽和疼痛递质，位于胃肠道。 SP可引起人胃肠外植体中Cl(-)的分泌。然而，其在隐孢子虫病中的作用尚未得到充分研究。分别通过逆转录-PCR、免疫组织化学和酶联免疫吸附测定法测定小隐孢子虫感染前后猕猴的空肠样本中 SP 和 SP 受体 mRNA 和蛋白质水平。通过尤斯室技术，利用感染小隐珠菌的猕猴组织，研究了 SP 在 Cl(-) 分泌和葡萄糖吸收不良等病理生理改变中的作用。微小念珠菌感染后，空肠样本中 SP 和 SP 受体 mRNA 和蛋白表达水平增加，并伴有基础离子分泌增加和葡萄糖吸收不良。用 SP 受体拮抗剂阿瑞吡坦（Emend；默克公司，新泽西州怀特豪斯站）对从受感染的猕猴获得的样本进行体外处理，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。我们的研究结果提出了使用 SP 受体拮抗剂治疗隐孢子虫病相关症状的可能性。