Mechanisms of growth control in developing Drosophila epithelia

果蝇上皮发育中的生长控制机制

基本信息

批准号：
10001356
负责人：
Kenneth H Moberg
金额：
$ 30.55万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-06 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10001356
关键词：
Address Adhesives Adolescent Adult Alleles Apical Apoptosis Area Binding Biology Cadherins Cancerous Cell Nucleus Cell Proliferation Cell Survival Cells Complex Cues Data Development Disease Drosophila genus Drosophila melanogaster Ecdysone Ecdysterone Elements Elephants Embryo Enhancers Enzymes Epithelial Epithelial Attachment Epithelium Estrogens Eye Fat Body Gene Expression Genes Genetic Genetic Transcription Goals Gonadal Steroid Hormones Growth Homeostasis Hormones Human Hyperplasia Injury Knowledge Larva Lead Learning Ligand Binding Domain Ligands Light Link Malignant Neoplasms Mediating Messenger RNA Mixed Function Oxygenases Modeling Mus Natural regeneration Newborn Infant Nuclear Nutrient Occupations Organ Organ Size Organism Pathologic Pathway interactions Pattern Phenocopy Phosphorylation Physiologic pulse Physiological Porifera Privatization Process Production Protein-Serine-Threonine Kinases Proteins Role Scallop Sequence-Specific DNA Binding Protein Signal Transduction Site Source Standardization Stress Testing Testosterone Time Tissues Transcription Coactivator Transgenic Organisms Translating Vertebrates Wing Work appendage base biochemical tools blastema disc regeneration ecdysone receptor experimental study fly human disease in vivo injured morphogens programs promoter receptor regenerative sensor steroid hormone tumor wound healing

项目摘要

Project Summary/Abstract The overall goal of this proposal is to understand how organisms as diverse as humans and the fruit flies use the same molecules to determine how large their organs will grow. The specific focus of this application is a protein that promotes growth called Yorkie. In our cells it is called Yap1, however it performs the same job in both species. When Yorkie/Yap1 is `active' in cells, it tells the cells to grow and divide, and thus generates many new cells. This makes tissues larger since they have more cells, but it can also lead to the growth of a cancerous tumor. We know a bit about how Yorkie/Yap1 become `active' but not enough to reliably predict when and where this happens, or how it promotes cancer when it becomes `active' all the time. We have found another protein that physically binds to Yorkie called Taiman, and we think Taiman may be key to understanding when and where Yorkie gets activated. Taiman itself has to get `activated', but in this case we know more about this happens. Taiman gets `activated' by the fly equivalent of the human sex hormones estrogen and testosterone. We think that when these hormones `activate' Taiman that they also activate Yorkie, and that this is an important way receive signals to grow and divide. The experiments we propose will address this hypothesis in a number of ways. We will test our idea that some cells can make their own fly `sex hormone' (called ecdysone), and that how much ecdysone they make controls when and where Taiman and Yorkie get activated in adolescent flies. This kind of patterned `activation' of Yorkie/Yap1 may be part of why we grow organs & appendages in the right places each time an embryo develops into a newborn baby, and by extension how inappropriate `actvation' of Yorkie/Yap1 at the wrong place and time can drive disease. We will also test another idea that cells with `activated' Yorkie and Taiman actually think they are part of a healing wound and start the process of regeneration to fill in the missing cells and tissue. Although we use flies to study these ideas, we remain confident that much of what we learn will teach us about how all of the proteins work in our cells.

项目概要/摘要该提案的总体目标是了解人类和果蝇等多种生物体如何利用相同的分子来决定它们的器官会生长多大。该应用程序的具体重点是促进生长的蛋白质称为约克。在我们的细胞中，它被称为 Yap1，但它在两个物种。当 Yorkie/Yap1 在细胞中“活跃”时，它会告诉细胞生长和分裂，从而产生许多新细胞。这使得组织变得更大，因为它们有更多的细胞，但它也可能导致细胞的生长癌性肿瘤。我们对 Yorkie/Yap1 如何变得“活跃”有一些了解，但还不足以可靠地预测这种情况发生的时间和地点，或者当它一直“活跃”时它如何促进癌症。我们发现了另一种与约克夏犬物理结合的蛋白质，称为 Taiman，我们认为 Taiman 可能是了解约克夏何时何地被激活的关键。 Taiman 本身必须被“激活”，但是在这个我们对这种情况有更多了解的情况发生。泰曼被相当于人类性别的苍蝇“激活” 激素雌激素和睾酮。我们认为，当这些激素“激活”泰曼时，它们也会激活约克夏，这是接收生长和分裂信号的重要方式。我们提出的实验将以多种方式解决这一假设。我们将测试我们的想法一些细胞可以为自己的苍蝇制造“性激素”（称为蜕皮激素），以及它们制造多少蜕皮激素控制泰曼和约克在青春期果蝇中被激活的时间和地点。这种模式化的“激活” Yorkie/Yap1 的基因可能是我们每次胚胎时在正确的位置生长器官和附属物的部分原因发育成新生婴儿，进而推论 Yorkie/Yap1 的不适当“激活”是如何错误的地点和时间会导致疾病。我们还将测试另一个想法，即具有“激活”约克和泰曼的细胞实际上认为它们是愈合伤口的一部分并开始再生过程以填补缺失的细胞和组织。尽管我们用苍蝇来研究这些想法，但我们仍然相信我们学到的大部分内容将教我们所有蛋白质如何在我们的细胞中发挥作用。