TGF-beta regulation of cell proliferation and differentiation in C. elegans

描述（申请人提供）：细胞增殖和细胞命运规范之间的协调是发育的基础，在癌症中这两个过程都被错误调节。虽然已知许多调节这些过程的分子途径，但它们在整个生物体环境中的相互作用知之甚少。研究者的长期目标是了解秀丽隐杆线虫中生殖系增殖控制和细胞命运规范的发育和分子基础，作为这种相互作用的一般模型。大多数动物的生殖细胞，包括哺乳动物，在发育过程中大量增殖。这种增殖是产生足够的成年配子所必需的。最近，她发现了TGF-¿信号通路在促进秀丽隐杆线虫幼虫种系增殖中的作用。初步数据表明，这一作用不同于之前所描述的同种TGF-¿通路在决策过程中的作用，该通路非自主地作用于种系细胞。研究者建议描述缺陷背后的细胞机制。此外，她的数据揭示了在这种情况下高度保守的TGF-¿和Notch信号通路之间的遗传相互作用。Se提出验证关于它们分子相互作用的一个特定假设：TGF-¿信号影响Notch配体的表达。如果数据反驳了她的假设，研究者将采取更公正的方法，开始确定TGF-¿信号对种系增殖影响的细胞和分子基础。这些研究可能会为细胞增殖控制的一般方面提供广泛适用的结果和见解，进一步了解细胞发育的基本情况，并可能对癌症产生影响。

DESCRIPTION (Provided by Applicant): The coordination between cell proliferation and cell fate specification is fundamental to development and both processes are misregulated in cancer. While many molecular pathways are known that regulate these processes, their interactions in the whole-organism context are poorly understood. The investigator's long-term goal is to understand the developmental and molecular basis for the control of germline proliferation and cell fate specification in C. elegans as a general model for this interaction. The germ cells of most animals, including mammals, proliferate extensively during development. This proliferation is required to produce adequate adult gamete production. Recently, she discovered a role for the TGF-¿ signaling pathway in promoting C. elegans larval germline proliferation. Preliminary data suggest that this role is distinct from the previously characterized role for the same TGF-¿ pathway during the dauer decision, and that the pathway acts germline non-autonomously. The investigator proposes to characterize the cellular mechanisms underlying the defect. In addition, her data reveal a genetic interaction between the highly-conserved TGF-¿ and Notch signaling pathways in this context. Se proposes to test a specific hypothesis regarding their molecular interaction: that TGF-¿ signaling influences Notch ligand expression. Should the data refute her hypothesis, the investigator will take more unbiased approaches to begin to determine the cellular and molecular basis for the effect of TGF-¿ signaling on germline proliferation. These studies will likely provide broadly applicable results and insights into general aspects of cell proliferation control, furthering a basic understanding of development and possibly yielding implications for cancer. PROJECT NARRATIVE: The TGF-¿ and Notch cell signaling pathways are highly conserved in animals and govern many important cellular processes during development, including cell proliferation and cell fate specification. These processes and signaling pathways are implicated in many diseases, especially cancer. The investigator recently discovered a new role for TGF-¿ in germ cell proliferation in C. elegans. She proposes to use this simple model organism to investigate the interaction between TGF-¿ signaling and the Notch pathway as they impinge on germ cell proliferation and differentiation.