Substance P in pathogenesis of cryptosporidiosis in AIDS

P物质在艾滋病隐孢子虫病发病机制中的作用

• 批准号: 6755897
• 负责人: PREMA ROBINSON
• 金额: $ 20.33万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-05 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6755897
• 关键词: Cryptosporidium; Macaca mulatta; biopsy; chloride ion; cryptosporidiosis; diarrhea; disease /disorder model; gastrointestinal epithelium; gastrointestinal sign /symptom; gene expression; ileum; membrane permeability; messenger RNA; neuroimmunomodulation; neuropeptide receptor; pathologic process; protein quantitation /detection; secretion; simian AIDSs; simian immunodeficiency virus; substance P; voltage /patch clamp

DESCRIPTION (provided by applicant): Cryptosporidiosis, caused by the protozoan parasite, Cryptosporidium parvum, is self-limited in normal hosts but can cause life threatening, chronic diarrhea in AIDS patients. No safe and effective treatment has been successfully developed for cryptospofidiosis associated with advanced AIDS. C. parvum infection causes intestinal physiologic changes like, increased chloride anion secretion (CI) and epithelial barrier disruption that leads to watery diarrhea. Substance P (SP), a neuropeptide, is a pain transmitter and can cause C1- ion secretion in human intestinal explants. We have previously studied SP expression in jejunal biopsies of AIDS patients with natural severe cryptosporidiosis and normal volunteers experimentally challenged with C. parvum (mild disease). SP expression was stronger in AIDS patients compared to normal volunteers with mild self-limited cryptosporidiosis. We hypothesize that SP is a key mediator of chronic intestinal symptoms in AIDS associated cryptosporidiosis. We also hypothesize that SP expression will be elevated in intestinal tissues of immunodeficient hosts because of cryptosporidiosis infection, HIV infection alone will not cause increased SP expression. To verify these hypotheses, we propose to use an immunodeficient animal model of cryptosporidiosis, ie. primates with AIDS (after experimental SIV infection) and cryptosporidiosis as an opportunistic naturally occurring infection. Advantage of an animal model is that, it is easier to procure large tissue samples from an animal model to that from AIDS patients with cryptosporidiosis, and, studies aimed at defining molecular targets responsible for disease pathogenesis and initial therapeutic testing of specific antagonists can best be studied using animal derived tissues. The goal of this project is to test the hypothesis that SP mediates severe symptoms of cryptosporidiosis in immunodeficient hosts. Specific aim 1: To determine if intestinal SP is upregulated in immunodeficient animals with chronic naturally infected cryptosporidiosis as compared to immunodeficient animals without cryptosporidiosis or normal immunocompetent macaques with subclinical experimental cryptosporidiosis. Ileal expression of SP mRNA and protein levels will be compared between immunodeficient macaques (with AIDS) with and without naturally occurring C. parvum infection and in normal macaques with and without subclinical experimental C. parvum infection. Specific aim 2: To test the hypothesis that SP is a key factor that mediates intestinal physiological alterations that lead to watery diarrhea in naturally occurring chronic cryptosporidiosis associated with immunodeficient hosts. C1- ion secretion and barrier integrity will be compared between ileal tissues from SIV infected macaques (with AIDS) with and without naturally occurring C. parvum infection in the presence and absence of SP receptor antagonist by the Ussing chamber technique. These studies will determine the role of SP in the pathogenesis of C. parvum induced diarrhea. Evidence implicating SP in the disease process would support the use of SP receptor antagonists as a therapy for the life threatening illness associated with AIDS related cryptosporidiosis and perhaps other intestinal pathogens.

描述（由申请人提供）：隐孢子虫病由原生动物寄生虫小隐孢子虫引起，在正常宿主中具有自限性，但在艾滋病患者中可能导致危及生命的慢性腹泻。对于与晚期艾滋病相关的隐孢子虫病，尚未成功开发出安全有效的治疗方法。小隐孢子虫感染会引起肠道生理变化，例如氯阴离子分泌 (CI) 增加和上皮屏障破坏，从而导致水样腹泻。 P 物质 (SP) 是一种神经肽，是一种疼痛递质，可引起人肠道外植体分泌 C1- 离子。我们之前研究过患有天然严重隐孢子虫病的艾滋病患者和接受小隐孢子虫实验攻击的正常志愿者（轻度疾病）的空肠活检中的 SP 表达。与患有轻度自限性隐孢子虫病的正常志愿者相比，艾滋病患者的 SP 表达更强。我们假设 SP 是艾滋病相关隐孢子虫病慢性肠道症状的关键介质。我们还假设免疫缺陷宿主的肠道组织中SP表达会因隐孢子虫感染而升高，单独的HIV感染不会引起SP表达升高。为了验证这些假设，我们建议使用隐孢子虫病的免疫缺陷动物模型，即。患有艾滋病（实验性 SIV 感染后）和隐孢子虫病的灵长类动物作为机会性自然发生的感染。动物模型的优点在于，更容易从动物模型中获取大量组织样本，而从患有隐孢子虫病的艾滋病患者那里获取大量组织样本，并且旨在确定负责疾病发病机制的分子靶标和特定拮抗剂的初始治疗测试的研究可以最好使用动物来源的组织进行研究。该项目的目标是检验 SP 在免疫缺陷宿主中介导隐孢子虫病严重症状的假设。具体目标 1：确定患有慢性自然感染隐孢子虫病的免疫缺陷动物与没有隐孢子虫病的免疫缺陷动物或患有亚临床实验性隐孢子虫病的正常免疫功能正常猕猴相比，肠道 SP 是否上调。将在有和没有自然发生的小小念珠菌感染的免疫缺陷猕猴（患有艾滋病）和有或没有亚临床实验性小念珠菌感染的正常猕猴之间比较SP mRNA和蛋白质水平的回肠表达。具体目标 2：检验以下假设：SP 是介导肠道生理改变的关键因素，导致与免疫缺陷宿主相关的自然发生的慢性隐孢子虫病导致水样腹泻。将通过尤斯室技术，在存在和不存在 SP 受体拮抗剂的情况下，比较来自 SIV 感染的猕猴（患有艾滋病）的回肠组织之间的 C1- 离子分泌和屏障完整性，其中有和没有自然发生的小小念珠菌感染。这些研究将确定 SP 在微小念珠菌引起的腹泻发病机制中的作用。表明 SP 参与疾病过程的证据将支持使用 SP 受体拮抗剂作为治疗与艾滋病相关的隐孢子虫病以及其他肠道病原体相关的危及生命的疾病的疗法。

项目成果

Substance P receptor antagonism for treatment of cryptosporidiosis in immunosuppressed mice.

P物质受体拮抗剂用于治疗免疫抑制小鼠的隐孢子虫病。

• DOI: 10.1645/ge-1458.1
• 发表时间: 2008
• 期刊: The Journal of parasitology
• 作者: Robinson,Prema;MartinJr,Protacio;Garza,Armandina;D'Souza,Melinda;Mastrangelo,Mary-Ann;Tweardy,David
• 通讯作者: Tweardy,David

Infection of immunocompetent mice with acid-water-pretreated Cryptosporidium parvum results in weight loss, and intestinal (structural and physiological) alterations.

用酸水预处理的小隐孢子虫感染免疫活性小鼠会导致体重减轻和肠道（结构和生理）改变。

• DOI: 10.1007/s00436-007-0785-3
• 发表时间: 2008
• 期刊: Parasitology research
• 影响因子: 2
• 作者: Garza,Armandina;Castellanos-Gonzalez,Alejandro;Castenallos-Gonzalez,Alejandro;Griffiths,Jeffrey;Robinson,Prema
• 通讯作者: Robinson,Prema