A New Signaling Pathway for Imaginal Cell Proliferation

成虫细胞增殖的新信号通路

• 批准号: 6619433
• 负责人: ALLEN D SHEARN
• 金额: $ 32.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6619433
• 关键词: Drosophilidae; arthropod genetics; biological signal transduction; cell proliferation; developmental genetics; fat body; growth factor; growth factor receptors; imaginal disc; invertebrate embryology; laboratory rabbit; temperature sensitive mutant

DESCRIPTION (Applicant's Description): During larval development Drosophila imaginal discs grow by normal cell division, whereas most larval cells grow by hypertrophy. Analysis of the consequences of mutations in the minidiscs gene and of targeted minidiscs expression has revealed that imaginal cell proliferation, but not larval cell growth, is regulated by a diffusible factor secreted by the larval fat body that has been named minidiscs dependent growth factor or MDGF. The long term goal of the proposed project is to elucidate the mechanism by which MDGF regulates the growth of distant target tissues, the imaginal discs. In humans, there are well known factors that are secreted into the circulatory system and regulate the growth of distant target tissues. As such this research is relevant to human developmental defects such as birth defects and cancer that are associated with abnormal levels of these secreted factors. Three specific aims are addressed in this proposal. 1) Four genes have been identified as candidates for ones whose products are required in the fat body for the synthesis, activation, and/or secretion of MDGF. The first candidate gene, compact discs (cds), encodes an entirely novel protein. The hypothesis to be tested is that the CDS protein acts in the fat body downstream of minidiscs function in the pathway leading to secretion of MDGF. The second candidate gene encodes a protein that is likely to be the regulatory subunit of the MND transporter. We will test the hypothesis that it is component of a heterodimer with MND and acts in parallel with minidiscs. The products of the two other candidate genes will be identified and their potential role will be analyzed using approaches similar to ones we apply to the study of compact discs. 2) The Imaginal Disc Growth Factors and Fat Body Derived Growth Factor will be evaluated as candidates for MDGF. 3) Mutational screens for dominant modifiers of a temperature sensitive minidiscs mutation will be used to identify the receptor for MDGF and downstream signaling components that respond to activation of the receptor in imaginal discs by causing or allowing cell proliferation. A pilot screen has yielded several putative suppressor mutations.

描述（申请人的描述）：在幼虫发展果蝇期间 想象中的椎间盘通过正常细胞分裂生长，而大多数幼虫细胞通过 肥大。分析Minidiscs基因突变的后果 有针对性的小型盘表达表明，想象中的细胞 增殖，但不是幼虫细胞生长，受到扩散因子的调节 由幼虫脂肪体分泌 因子或MDGF。拟议项目的长期目标是阐明 MDGF调节遥远目标组织的生长的机制， 想象中的光盘。在人类中，有一些已知的因素被分泌到 循环系统并调节遥远目标组织的生长。作为 这样的研究与人类发育缺陷（例如出生）有关 与这些分泌的异常相关的缺陷和癌症 因素。在本提案中解决了三个具体目标。 1）四个基因被确定为产品的候选者 在脂肪体中需要进行合成，激活和/或分泌 MDGF。第一个候选基因紧凑型椎间盘（CD）编码一个完全新颖的 蛋白质。要检验的假设是CD蛋白在脂肪中起作用 Minidiscs下游的身体在该路径中起作用，导致分泌 MDGF。第二个候选基因编码可能是 MND转运蛋白的调节亚基。我们将检验以下假设 是具有MND的异二聚体的组成部分，并与Minidiscs并行作用。这 将确定其他两个候选基因的产品，并 将使用类似于我们适用的方法来分析潜在角色 紧凑椎间盘的研究。 2）想象的椎间盘生长因子和脂肪体衍生的生长因子将是 评估为MDGF的候选者。 3）温度敏感的主要修饰符的突变筛选 Minidiscs突变将用于识别MDGF的受体和 对受体激活反应的下游信号传导成分 通过引起或允许细胞增殖来进行想象。飞行员屏幕有 产生了几个推定的抑制突变。