Molecular Targets of Blocking Malaria Transmission

疟疾继续扩大，成为全世界的一个主要公共卫生威胁。毒品的泛滥 抗药性疟疾和缺乏有效的疫苗使替代和补充办法 疟疾控制日益重要。这项研究计划的总主题一直是开发 如何通过干扰P/AS/DOC//UM-蚊子来阻断疟疾传播的机械概念 蚊子中肠内的分子相互作用，特别是在运动细胞-周围基质界面。这个 上个项目期表明，通过抗体或抗体干扰疟原虫几丁质酶(S)的功能 几丁质酶基因缺失干扰了蚊虫的寄生虫感染性。作为持续努力的一部分， 继续描述运动疟原虫入侵蚊子的分子机制 MidguCwe已经鉴定出第二个由鸡疫霉运动细胞分泌的几丁质酶，这是已知的唯一与鸡疫霉属同源的几丁质酶 恶性疟原虫几丁质酶，PfCHTI，和一种由动子分泌的血浆蛋白酶，一种我们 假设涉及到与几丁质酶(S)一起工作，以允许动细胞穿透围食性 蚊子中肠内的基质。支持这一建议的假设是，动感疟原虫 分泌几丁质酶和血浆蛋白，这两种酶都参与入侵蚊子中肠，或者是相加的 或者协同作用。这项竞争性更新提案有三个具体目标：1)确定机制 鸡疟原虫PgCHT2中恶性疟原虫PfCHTI几丁质酶同源基因促进卵子运动的研究 周围性基质的穿透；2)识别JP。鸡科动物运动杆菌产生的蛋白酶 介导鸡疟原虫几丁质酶PgCHTI的激活；以及3)确定疟原虫的作用 天冬氨酸蛋白酶(血浆蛋白)在蚊虫中肠运动入侵中的作用。这个项目将产生洞察力 探讨了P/asmod/um-蚊虫中肠相互作用的基本生物学过程，包括P/asmod/um-蚊子中肠的功能。 恶性疟原虫几丁质酶，PfCHTI，并为开发新的潜在途径提供科学基础 在脊椎动物宿主-蚊子媒介界面阻断疟疾传播。

Malaria continues to expand as a major public health threat throughout the world. The spread of drug resistant malaria and the lack of an effective vaccine make alternative and complementary approaches to malaria control increasingly important. The overall theme of this research program has been to develop mechanistic concepts of how to block malaria transmission by interfering with P/as/Doc//um-mosquito molecular interactions within the mosquito midgut, particular at the ookinete-peritrophix matrix interface. The last project period showed that interfering with the function of Plasmodium chitinase(s) by antibody or chitinase gene deletion interfered with parasite infectivity for the mosquito. As part of ongoing efforts to continue delineating molecular mechanisms by which the Plasmodium ookinete invades the mosquito midguCwe have identified a second P. gallinaceum ookinete-secreted chitinase, the only known ortholog of the P. falciparum chitinase, PfCHTI, and an ookinete-secreted plasmepsin, an aspartic protease that we hypothesize is involved working together with chitinase(s) to allow the ookinete to penetrate the peritrophic matrix within the mosquito midgut. The hypothesis underlying this proposal is that Plasmodium ookinetes secrete chitinases and plasmepsins that are both involved in invading the mosquito midgut, either additively or synergistically. This competitive renewal proposal h^is three specific aims: 1) To determine mechanisms by which the P. falciparum PfCHTI chitinase orthologi^e in P. gallinaceum, PgCHT2, facilitates ookinete penetration of the peritrophic matrix; 2) To identify thejP. gallinaceum ookinete-produced protease that mediates activation of the P. gallinaceum chitinase PgCHTI; and 3) To determine the role of Plasmodium aspartic proteases (plasmepsins) in ookinete invasion1of the mosquito midgut. This project will yield insight into basic biological processes of P/asmod/um-mosquito midgut interactions, including the function of the P. falciparum chitinase, PfCHTI, and provide the scientific basis for developing novel potential approaches to interrupting malaria transmission at the vertebrate host-mosquito vector interface.