INSECT DIURETIC HORMONES--STRUCTURES AND FUNCTION

昆虫有低压循环系统，需要利尿剂 通过马氏管控制尿的产生的激素。 我们 2004年，在昆虫中鉴定出第一种昆虫利尿激素（DH），天蛾（Manduca sexta DH）， 1989. 现在这个不断壮大的DH家族有十个成员（四个 与以前的资金确定），这是结构上同源的 促肾上腺皮质激素释放因子/sauvagine/尾加压素I肽家族。 CRF样DH序列的一个极其新颖的方面是， 在30-46个残基的氨基末端的一半具有同源区域 序列，并且在分子的羧基末端具有同源性，但存在缺口 在大多数序列的中间是必需的， 特米尼 序列中的这些空白应该会导致 相关昆虫DH的三维构象;奇怪的是， 除了三种已知的CRF样DH外，所有的CRF样DH都激活了 曼陀罗 我们建议研究分离和鉴定CRF样DH 来自南美锥虫病媒介Rhodnius prolixus和另外两种昆虫 物种 我们计划在R. prolixus与 教授伊恩果园，美国多伦多拥有这种病媒是 在美国受到严格控制。 我们还将研究成员的相对三维构象 通过计算机模拟和物理化学方法， 希望包括X射线晶体学 我们也希望了解更多 关于M。sexta和DH以及其他DH与它们的受体相互作用。 我们建议确定分子的哪一部分激活了 受体，并确定受体分子M的哪个部分。sexta DH结合。 对这个独特的神经肽家族的研究将提供信息 其可用于设计具有DH活性的小分子， 对控制吸血昆虫有很大的潜在用途。 类似物 的昆虫保幼激素（倍半萜类化合物）目前在商业上 作为极其安全的特定昆虫控制剂使用。

Insects have low pressure circulatory systems and require diuretic hormones to control production of urine by Malpighian tubules. We identified the first insect diuretic hormone (DH), Manduca sexta DH, in 1989. There are now ten members of this growing family of DH (four identified with prior funding), which are structurally homologous to the corticotropin releasing factor/sauvagine/urotensin I family of peptides. An extremely novel aspect of the sequences of the CRF-like DH is that they have homologous regions for the amino terminal half of the 30-46 residue sequence, and homology at the carboxyl terminus of the molecule but gaps are required in the middle of most sequences for good alignment of both termini. These gaps in the sequence should cause profound differences in the three dimensional conformation of the related insect DHs; curiously, all but three of the known CRF-like DH activate Malpighian tubules of Manduca sexta. We propose studies to isolate and identify CRF-like DH from Rhodnius prolixus, a vector of Chagas' disease, and two other insect species. We plan to do the work on R. prolixus in collaboration with Prof. Ian Orchard, U. of Toronto, as possession of this disease vector is strictly controlled in the US. We will also study the relative three dimensional conformation of members of this family of DH by computer modeling and by physico-chemical methods, hopefully including X-ray crystallography. We also hope to learn more about how M. sexta and DH, and other DH, interact with their receptors. We propose to determine exactly what part of the molecule activates the receptor, and to determine to what part of the receptor molecule M. sexta DH binds. Studies on this unique family of neuropeptides will provide information which may be of utility in designing small molecules with DH activity, potentially of great use for control of blood-sucking insects. Analogues of insect juvenile hormones (sesquiterpenoids) are currently in commercial use as extremely safe, specific insect control agents.