Cell signaling in development and regeneration

细胞间通讯在胚胎发育和成人组织动态平衡中起着核心作用 放松管制会导致人类疾病，包括出生缺陷和癌症。因此，了解如何 细胞外信号被传递和整合，以控制细胞的增殖和分化 在生物医学研究中，发展、组织动态平衡和再生是至关重要的。这个 这个团队的首要目标是了解信号网络如何控制器官发育和 再生，重点是Hedgehog(HH)、Hippo和BMP信号通路。HH信令 控制着从果蝇到人类等物种的许多关键发育过程及其异常 活性与许多人类癌症有关，包括髓母细胞瘤和基底细胞癌。 癌症。HH通过gpcr家族受体发出的保守信号级联起作用。 对锌指转录因子Ci/Gli的平滑(Smo)，但Smo如何激活Ci/Gli仍然很差 明白了。在这项提案中，该团队将结合遗传学、生物化学、细胞生物学和生物物理学 探索管理SMO运输、磷酸化依赖和- Ci/Gli的独立激活，以及Smo与Ci/Gli之间的分子联系。河马的路径是 最初在果蝇中发现，在组织生长和器官大小的控制中起着保守的作用，通过 同时调节细胞的增殖和存活。对河马信号的放松管制也是 与多种人类癌症有关。尽管它在发展和疾病方面至关重要，但 生理条件下河马信号转导机制的研究 病理情况仍然不完全清楚。该团队已经开发出一种遗传修饰物屏幕 使他们能够识别新的和进化上保守的河马途径调节因子。团队将继续 研究新发现的成分调节河马通路活性的机制。 控制器官大小和组织再生。该团队率先将果蝇的成体肠道用作 研究干细胞自我更新、增殖和分化如何调控的模型系统 在组织动态平衡和再生过程中，发现河马、HH和BMP信号对 干细胞活性的调节。在之前的资助期间，该团队还建立了果蝇成虫 以肠道为模型研究损伤后体内重编程并开始探索其分子机制 托换。在这项拟议的研究中，该团队将研究其他细胞外在和内在因素如何 与BMP信号联合作用，促进干细胞自我更新，探索遗传和细胞 控制将完全分化的细胞重新编程为成体干细胞的机制 受伤。从这项研究中获得的知识将对发育生物学产生重要影响， 癌症生物学和再生医学。

Cell-cell communication plays a central role in embryonic development and adult tissue homeostasis and its deregulation leads to human diseases including birth defects and cancers. Therefore, understanding how extracellular signals are transduced and integrated to control cell proliferation and differentiation during development, tissue homeostasis and regeneration is of central importance in biomedical research. The overarching goal of this team is to understand how signaling networks control organ development and regeneration, with an emphasis on Hedgehog (Hh), Hippo, and BMP signaling pathways. Hh signaling controls many key developmental processes in species ranging from Drosophila to human and its abnormal activity has been implicated in numerous human cancers including medulloblastoma and basal cell carcinoma. Hh acts through a conserved signaling cascade emanating from the GPCR family receptor Smoothened (Smo) to the Zn-finger transcription factor Ci/Gli but how Smo activates Ci/Gli is still poorly understood. In this proposal, the team will combine genetics, biochemistry, cell biology, and biophysical approaches to explore conserved mechanisms governing Smo trafficking, phosphorylation-dependent and - independent activation of Ci/Gli, and the molecular links between Smo and Ci/Gli. The Hippo pathway was initially discovered in Drosophila and plays a conserved role in the control of tissue growth and organ size by simultaneously regulating cell proliferation and survival. Deregulation of Hippo signaling has also been implicated in many types of human cancer. Despite its central importance in development and diseases, the mechanisms underlying Hippo pathway regulation under physiological conditions or deregulation under pathological conditions remain incompletely understood. The team has developed a genetic modifier screen allowing them to identify novel and evolutionarily conserved Hippo pathway regulators. The team will continue to investigate the mechanisms by which the newly identified components regulate Hippo pathway activity in organ size control and tissue regeneration. The team has pioneered the use of Drosophila adult intestine as a model system to investigate how stem cell self-renewal, proliferation, and differentiation are regulated during tissue homeostasis and regeneration, and identified Hippo, Hh and BMP signaling as essential for the regulation of stem cell activity. In the previous funding period, the team has also established Drosophila adult intestine as a model to study in vivo reprogramming after injury and began to explore the molecular underpinning. In the proposed study, the team will investigate how other cell extrinsic and intrinsic factors acts in conjunction with BMP signaling to promote stem cell self-renewal and explore the genetic and cellular mechanisms that control the reprogramming of fully differentiated cells to adult stem cells in response to injury. The knowledge gained from this study will have important implications for developmental biology, cancer biology, and regenerative medicine.