Function of Mipp1 in Regulating Drosophila Trachea Tube Size and Branch Migration

Mipp1在调节果蝇气管管大小和分支迁移中的作用

• 批准号: 7998429
• 负责人: Yim Ling Cheng
• 金额: $ 3.58万
• 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: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7998429
• 关键词: Affect; Animals; Biological Models; Biological Process; Blood Circulation; Blood Vessels; Cardiovascular Diseases; Cell physiology; Defect; Development; Dorsal; Drosophila genus; Embryo; Enzymes; Family; Generations; Genes; Genetic Transcription; Goals; Heart; Inositol; InsP5; Intestines; Kidney; Knock-out; Lead; Learning; Length; Lung; Medial; Molecular; Organ; Organogenesis; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Polycystic Kidney Diseases; Polyphosphates; Process; Production; Regulation; Role; Second Messenger Systems; System; Testing; Tissues; Trachea; Tube; Tubular formation; Tumor Angiogenesis; human disease; insight; migration; mutant; novel; overexpression; protein function; public health relevance; second messenger; tumor

DESCRIPTION (provided by applicant): Tube formation is an important process in the development of many organs, including the lung, kidney, intestine, and heart, so it is critical to understand this process at both the cellular and molecular level. The goal of this proposal is to elucidate the role of multiple inositol polyphosphate phosphatase (Mipp1) in Drosophila trachea development, which is one of the best model systems for studying tubular organogenesis. Mipps are the main enzymes to dissipate the high order inositol polyphosphates (InsP), which are important second messengers for many important cellular processes. The biological function of Mipps is very poorly understood. mipp1 was identified as a downstream target of Trachealess (Trh), a critical transcription regulating the entire process of trachea formation. A knockout of mipp1 was successfully generated and its phenotypic characterization revealed significant dorsal trunk elongation and ganglionic branch mismigration defects. These preliminary results lead to the hypothesis that Mipp1 regulates the production of molecules involved in limiting dorsal trunk length and directing ganglionic branch migration. Part A of specific aim 1 will define the role of Mipp1 in tracheal development by analyzing the tracheal phenotypes associated with the loss and overexpression of Mipp1. Part B of specific aim 1 will reveal whether Mipp1 functions through the known pathways that affect tracheal dorsal trunk tube size control and ganglionic branch migration or through a novel pathway(s). Specific aim 2 will test if Drosophila Mipp2 compensates for Mipp1 activity by comparing the tracheal phenotypes of mipp1 knockout and mipp1 mipp2 double null mutants. Specific aim 3 will reveal whether Mipp1 functions through the generation of InsP4, InsP3 from InsP5 and InsP6 or through the generation of 2- phosphogylcerate from 2, 3-biphosphoglycerate to regulate tube size control and branch migration. The genes encoding enzymes in parallel pathways will be manipulated to build up Mipp1 substrates or products to learn which molecules are relevant to the tracheal defects observed in mipp1mutants. The analysis of Mipp function in the very tractable system of the Drosophila embryonic trachea is likely to provide insight into how this highly conserved family of proteins functions in higher animals. PUBLIC HEALTH RELEVANCE: Common human diseases related to tube size and regulation of branch migration include cardiovascular disease, polycystic kidney disease, and tumor angiogenesis. Mipp1, a novel enzyme whose expression is regulated by Trachealess, a major regulator of tube formation in Drosophila, may turn out to be a novel target for manipulating tube size and/or branch migration. Such manipulations have important medial implications such as enlarging the blood vessels to increase circulation to ischemic tissues or inhibiting blood vessel formation and targeting in tumors.

描述(申请人提供)：管状形成是许多器官发育的重要过程，包括肺、肾、肠和心脏，因此在细胞和分子水平上了解这一过程是至关重要的。本研究的目的是阐明多重肌醇多聚磷酸酶(Mipp1)在果蝇气管发育中的作用，这是研究管状器官发生的最佳模型系统之一。MIPPS是消耗高阶肌醇多磷酸(INSP)的主要酶，而INSP是许多重要细胞过程的重要第二信使。目前对Mipps的生物学功能知之甚少。Mipp1被确定为TracHealth ess(TRH)的下游靶标，TRH是调节气管形成整个过程的关键转录。Mipp1基因被成功地敲除，其表型特征显示明显的背干延长和神经节支错位移动缺陷。这些初步结果导致假设，Mipp1调节参与限制背干长度和指导神经节分支迁移的分子的产生。具体目标1的A部分将通过分析与Mipp1的缺失和过表达相关的气管表型来定义Mipp1在气管发育中的作用。具体目标1的B部分将揭示Mipp1是通过影响气管背干管大小控制和神经节支迁移的已知途径发挥作用，还是通过新的途径发挥作用(S)。特殊目的2将通过比较mipp1基因敲除和mipp1 mipp2双零突变的气管表型来测试果蝇mipp2是否补偿mipp1的活性。具体目标3将揭示Mipp1是通过由InsP5和InsP6产生InsP4、InsP3，还是通过由2，3-双磷酸甘油酸酯产生2-磷酸甘油酸酯来调节管径控制和分支迁移。平行通路中编码酶的基因将被操纵来构建Mipp1底物或产物，以了解哪些分子与在mipp1突变体中观察到的气管缺陷有关。对果蝇胚胎气管这个非常容易处理的系统中MIPP功能的分析可能会为深入了解这一高度保守的蛋白质家族在高等动物中的功能提供线索。 公共卫生相关性：与管子大小和分支迁移调节相关的常见人类疾病包括心血管疾病、多囊肾病和肿瘤血管生成。Mipp1是一种新的酶，其表达受果蝇管形成的主要调节因子TracHealth调控，可能成为操纵管大小和/或分支迁移的新靶点。这种操作具有重要的医学意义，如扩大血管以增加对缺血组织的循环，或抑制肿瘤中的血管形成和靶向。