Characterization of the An. gambiae LL3/SRPN6 pathway in response to Plasmodium i

An 的表征。

• 批准号: 8242861
• 负责人: Ryan C. Smith
• 金额: $ 6.02万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242861
• 关键词: Binding Sites; Biochemical; Biological Assay; Cessation of life; Computer Simulation; Consensus; Contracts; Culicidae; DNA Binding; Development; Disease; Epithelium; Event; Gene Expression; Genes; Genetic; Genome; Goals; Immune; Immune response; Immune system; Immunity; Immunoprecipitation; In Vitro; Insecta; Intervention; Lead; Malaria; Mediating; Methodology; Methods; Midgut; Molecular; Molecular Target; Nucleic Acid Regulatory Sequences; Organism; Parasites; Pathway interactions; Peptide Hydrolases; Plasmodium; RNA Interference; Regulation; Risk; Role; Salivary Glands; Serine Protease; Serine Proteinase Inhibitors; Serpins; Staging; Transcriptional Activation; Transcriptional Regulation; Work; immune activation; insight; novel; novel strategies; parasite invasion; prevent; promoter; protein aminoacid sequence; protein protein interaction; research study; response; success; transcription factor; transmission process

DESCRIPTION (provided by applicant): Every year, more than one million deaths are attributed to malaria and approximately 40% of the world's six billion people remain at risk of contracting the disease. Such staggering numbers make the development of an effective control strategy of the highest importance. One proposed methodology for disease intervention capitalizes on the obligate requirement for development of the malaria parasite (Plasmodium) within the mosquito for malaria transmission. Recent studies have demonstrated that a mosquito serine protease inhibitor, serpin 6 (SRPN6), limits parasite success during the invasion of the midgut and salivary gland epithelium. Serpins are conserved components of many organisms and have been implicated in a variety of cellular events including the regulation of the insect immune response. During both invasive stages of parasite development, the expression of SRPN6 is dramatically increased in response to Plasmodium infection, yet the molecular mechanisms that lead to this response remain unknown. In Specific Aim 1, I will identify the protease target of SRPN6 and thus begin to define the mechanism by which SRPN6 impairs parasite development. In Specific Aim 2, I will elucidate the molecular components that lead to the transcriptional activation of the SRPN6 gene. In Specific Aim 3, I will determine the role of a transcription factor (LL3), a known regulator of SRPN6 expression in response to Plasmodium midgut invasion, in the transcriptional regulation of other co-regulated immune genes. Through these experiments I hope to provide novel insights into mosquito immunity in response to parasite invasion that may lead to new molecular targets for disease intervention strategies.

描述(申请人提供)：每年有100多万人死于疟疾，全世界60亿人口中约40%的人仍然面临感染这种疾病的风险。如此惊人的数字使得制定有效的控制战略变得至关重要。一种拟议的疾病干预方法利用了在蚊子内发展疟疾寄生虫(疟原虫)以传播疟疾的预定要求。最近的研究表明，蚊子丝氨酸蛋白酶抑制剂丝氨酸丝氨酸蛋白酶6(SRPN6)在中肠和唾液腺上皮的入侵过程中限制了寄生虫的成功。Serpins是许多生物体的保守成分，参与了多种细胞事件，包括调节昆虫的免疫反应。在寄生虫发育的两个侵袭阶段，SRPN6的表达显著增加，以响应疟原虫的感染，但导致这种反应的分子机制尚不清楚。在特定的目标1中，我将确定SRPN6的蛋白酶靶标，从而开始定义SRPN6损害寄生虫发育的机制。在特定的目标2中，我将阐明导致SRPN6基因转录激活的分子成分。在特定的目标3中，我将确定转录因子(LL3)在其他共同调节的免疫基因的转录调控中的作用。LL3是一种已知的SRPN6表达调节因子，用于响应疟原虫中肠入侵。通过这些实验，我希望为蚊子免疫应对寄生虫入侵提供新的见解，这可能会为疾病干预策略带来新的分子靶点。

项目成果

Immunization against a merozoite sheddase promotes multiple invasion of red blood cells and attenuates Plasmodium infection in mice.

• DOI: 10.1186/1475-2875-13-313
• 发表时间: 2014-08-12
• 期刊: Malaria journal
• 影响因子: 3
• 作者: Smith RC;Colón-López DD;Bosch J
• 通讯作者: Bosch J

Plasmodium-Mosquito Interactions: A Tale of Roadblocks and Detours.

疟原虫与蚊子的相互作用：障碍和弯路的故事。

• DOI: 10.1016/b978-0-12-381387-9.00004-x
• 发表时间: 2010
• 期刊: Advances in insect physiology
• 作者: Smith,RyanC;Jacobs-Lorena,Marcelo
• 通讯作者: Jacobs-Lorena,Marcelo