Cell signaling in development and regeneration

发育和再生中的细胞信号传导

• 批准号: 10189084
• 负责人: Jin Jiang
• 金额: $ 88.75万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-06 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10189084
• 关键词: Adult; Basal cell carcinoma; Biochemistry; Biological Models; Biomedical Research; Cancer Biology; Cell Communication; Cell Differentiation process; Cell Proliferation; Cell Survival; Cells; Cellular biology; Congenital Abnormality; Development; Developmental Biology; Developmental Process; Disease; Drosophila genus; Embryonic Development; Erinaceidae; Etiology; Family; Fingers; Funding; G-Protein-Coupled Receptors; Genetic; Goals; Growth; Homeostasis; Human; Injury; Intestines; Intrinsic factor; Knowledge; Link; Malignant Neoplasms; Modeling; Molecular; Natural regeneration; Organ Size; Pathologic; Pathway interactions; Phosphorylation; Physiological; Play; Regenerative Medicine; Regulation; Role; Signal Pathway; Signal Transduction; Therapeutic; Tissues; adult stem cell; biophysical techniques; cancer therapy; extracellular; human disease; in vivo; insight; medulloblastoma; novel; organ growth; organ regeneration; receptor; response to injury; smoothened signaling pathway; stem cell self renewal; stem cells; tissue regeneration; trafficking; transcription factor

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.

细胞间通讯在胚胎发育和成体组织稳态及其中发挥着核心作用 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 细胞外信号被转导和整合以控制细胞增殖和分化 发育、组织稳态和再生在生物医学研究中至关重要。这 该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 信号传导 控制从果蝇到人类的物种的许多关键发育过程及其异常 活性与多种人类癌症有关，包括髓母细胞瘤和基底细胞瘤 癌。 Hh 通过 GPCR 家族受体发出的保守信号级联起作用 对 Zn 指转录因子 Ci/Gli 进行了平滑处理 (Smo)，但 Smo 如何激活 Ci/Gli 仍不清楚 明白了。在该提案中，该团队将结合遗传学、生物化学、细胞生物学和生物物理学 探索控制 Smo 贩运、磷酸化依赖性和 - 的保守机制的方法 Ci/Gli 的独立激活，以及 Smo 和 Ci/Gli 之间的分子联系。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发挥保守作用 同时调节细胞增殖和存活。 Hippo 信号的放松管制也已 与多种人类癌症有关。尽管它在发育和疾病方面具有核心重要性， 生理条件下 Hippo 通路调节或解除调节的机制 病理状况仍未完全了解。该团队开发了基因修饰筛选 使他们能够识别新颖且进化保守的 Hippo 通路调节因子。团队将继续 研究新发现的成分调节 Hippo 通路活性的机制 器官大小控制和组织再生。该团队率先利用果蝇成体肠道作为 研究干细胞自我更新、增殖和分化如何调节的模型系统 在组织稳态和再生过程中，并确定 Hippo、Hh 和 BMP 信号对于组织稳态和再生至关重要 干细胞活性的调节。在之前的资助期间，团队还建立了果蝇成虫 以肠为模型研究损伤后体内重编程，并开始探索分子机制 支撑。在拟议的研究中，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 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。