Genetic Control of Non-Autonomous Survival in Drosophila

描述(申请人提供)：细胞/细胞通讯控制细胞生理学的许多方面，包括细胞增殖、细胞分化和细胞死亡/存活。然而，多细胞生物的复杂性使得人们很难全面了解控制这些方面的所有细胞外信号机制。这项研究的重点是细胞外信号或非自主信号对细胞存活的控制。我们已经在肿瘤抑制基因中发现了突变，这种基因可以控制细胞外因子的分泌，从而促进邻近细胞的存活。这些研究揭示了细胞之间的相互作用，这与组织的动态平衡非常相关，异常可能与包括癌症在内的人类疾病的孤雌生殖直接相关。例如，含有这些肿瘤抑制基因突变克隆的动物的特征是组织过度生长和肿瘤样肿块。在其中一些突变体中，Notch活性被不适当地激活，以非自主的方式刺激增殖和存活。不适当的Notch激活被认为与许多人类癌症的发生有关。我们的数据表明，细胞增殖不足以产生肿瘤肿块；相反，增加细胞存活率是肿瘤充分发展所必需的。因此，了解控制非自主细胞存活的遗传和分子机制对于预防和治疗这些疾病至关重要。这项提议的主要目的是加深我们对非自主生存机制的理解。为此，我们使用了高度可及的遗传模式生物黑腹果蝇。我们的具体目标是：1.确定信号传递细胞中控制非自治细胞生存的基因。2.确定导致邻近细胞内控制细胞生存的信号分子分泌的机制。3.确定信号接收细胞中控制非自主生存的信号和机制。该项目将是第一个系统地识别所有控制有机体中非自主生存的基因和机制的方法。这些基因的特征可能对理解人类疾病具有重要意义，并可能有助于开发治疗这些疾病的药物和疗法。

DESCRIPTION (provided by applicant): Cell/cell communication controls many aspects of cellular physiology including cell proliferation, cell differentiation and cell death/survival. However, the complexity of multi-cellular organisms has made it difficult to obtain a comprehensive understanding of all extracellular signaling mechanisms controlling these aspects. This research project focuses on the control of cell survival by extracellular, or non-autonomous, signaling. We have identified mutants in tumor-suppressor-like genes that control the secretion of extra-cellular factors which promote the survival of neighboring cells. These studies reveal interactions between cells which are very relevant for tissue homeostasis, and abnormalities may be directly linked to the parthenogenesis of human diseases including cancer. For example, animals containing mutant clones of these tumor suppressor-like genes are characterized by tissue overgrowth and tumor-like masses. In some of these mutants, Notch activity is inappropriately activated which stimulates proliferation and survival in a non-autonomous manner. Inappropriate Notch activation has been implicated for the genesis of many human cancers. Our data demonstrate that cell proliferation is not sufficient for generation of the tumor masses; instead increased cell survival is necessary for full development of tumors. Therefore, an understanding of the genetic and molecular mechanisms that control non-autonomous cell survival is crucial for the prevention and treatment of these diseases. It is the main goal of this proposal to further our understanding about the mechanisms that regulate non-autonomous survival. For this purpose, we are using the highly accessible genetic model organism Drosophila melanogaster. Our specific aims are: 1. Identify the genes in the signal-sending cell that control non-autonomous cell survival. 2. Identify the mechanisms which lead to secretion of signaling molecules that control cell survival in neighboring cells. 3. Identify the signals and the mechanisms in the signal-receiving cell that control non-autonomous survival. This project will be the first systematic approach to identify all genes and mechanisms that control non- autonomous survival in any organism. The characterization of these genes may have significant implications for the understanding of human diseases, and may help developing drugs and therapies to treat these diseases.