Cell signaling in development and regeneration

发育和再生中的细胞信号传导

• 批准号: 10615843
• 负责人: Jin Jiang
• 金额: $ 88.83万
• 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/10615843
• 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; Proliferating; 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; 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-细胞通讯在胚胎发育和成体组织稳态及其发育过程中起着核心作用