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

描述（由申请人提供）：每年有100多万人死于疟疾，世界60亿人口中约有40%仍然面临感染这种疾病的风险。如此惊人的数字使制定有效的控制战略变得极为重要。一种拟议的疾病干预方法利用了蚊子体内疟疾寄生虫（疟原虫）为疟疾传播而发展的必然要求。最近的研究表明，蚊子丝氨酸蛋白酶抑制剂丝氨酸蛋白酶6 （SRPN6）在入侵中肠和唾液腺上皮时限制了寄生虫的成功。蛇蛋白是许多生物体的保守成分，涉及多种细胞事件，包括昆虫免疫反应的调节。在寄生虫发育的两个侵袭阶段，SRPN6的表达在对疟原虫感染的反应中显著增加，但导致这种反应的分子机制尚不清楚。在Specific Aim 1中，我将确定SRPN6的蛋白酶靶点，从而开始定义SRPN6损害寄生虫发育的机制。在Specific Aim 2中，我将阐明导致SRPN6基因转录激活的分子成分。在Specific Aim 3中，我将确定转录因子（LL3）在其他共调节免疫基因的转录调节中的作用。LL3是一种已知的SRPN6表达在响应中肠疟原虫入侵中的调节因子。通过这些实验，我希望对蚊子对寄生虫入侵的免疫反应提供新的见解，从而为疾病干预策略提供新的分子靶点。

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. PUBLIC HEALTH RELEVANCE: The transmission of malaria requires the mosquito host. By understanding the mechanisms of parasite invasion and subsequent mosquito immune response, novel strategies for malaria intervention can be developed. The characterization of an anti- parasitic pathway involved in mosquito immunity is outlined within this proposal, which may lead to the development of disease intervention strategies to prevent the spread of malaria.