Cell signaling in development and regeneration

细胞间通讯在胚胎发育和成体组织稳态中起着重要作用， 放松管制导致人类疾病，包括出生缺陷和癌症。因此，了解如何 细胞外信号被转导和整合以控制细胞增殖和分化， 在生物医学研究中，发育、组织稳态和再生是至关重要的。的 该团队的首要目标是了解信号网络如何控制器官发育， 再生，重点是Hedgehog（Hh），Hippo和BMP信号通路。hh信号 控制着从果蝇到人类的许多关键发育过程， 活性与许多人类癌症有关，包括成神经管细胞瘤和基底细胞癌。 carcinoma. Hh通过源自GPCR家族受体的保守信号级联起作用 Smoened（Smo）对锌指转录因子Ci/Gli的作用机制尚不清楚 明白在这项提案中，研究小组将联合收割机结合遗传学、生物化学、细胞生物学和生物物理学 探索Smo运输、磷酸化依赖性和 Ci/Gli的独立激活，以及Smo和Ci/Gli之间的分子连接。河马途径是 最初在果蝇中发现，在控制组织生长和器官大小方面起着保守的作用， 同时调节细胞增殖和存活。Hippo信号的失调也被认为是 与多种人类癌症有关。尽管它在发育和疾病中具有核心重要性， 生理条件下Hippo通路调节的潜在机制或 病理状况仍然不完全清楚。该团队开发了一种基因修饰筛选器 使他们能够识别新的和进化上保守的Hippo通路调节因子。该团队将继续 研究新鉴定的组分调节Hippo通路活性的机制， 器官大小控制和组织再生。该团队率先使用果蝇成年肠道作为 研究干细胞自我更新、增殖和分化如何受到调控的模型系统 在组织稳态和再生过程中，并确定Hippo，Hh和BMP信号传导是组织稳态和再生所必需的。 调节干细胞活性。在此前的资助期内，该团队还建立了果蝇成虫 肠作为模型，研究损伤后体内重编程，并开始探索其分子生物学机制。 托换在拟议的研究中，研究小组将调查其他细胞外在和内在因素如何影响细胞的生长。 与BMP信号传导结合作用，促进干细胞自我更新并探索遗传和细胞 控制完全分化细胞重编程为成体干细胞的机制， 损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.