Cell signaling in development and regeneration

发育和再生中的细胞信号传导

• 批准号: 9923670
• 负责人: Jin Jiang
• 金额: $ 86.02万
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923670
• 关键词: Adult; Apoptosis; Basal cell carcinoma; Biomedical Research; Cancer Biology; Cell Lineage; Cell surface; Chemicals; Complex; Development; Developmental Biology; Developmental Process; Disease; Drosophila genus; Embryonic Development; Epithelial; Epithelium; Erinaceidae; Etiology; Genetic; Goals; Growth; Homeostasis; Human; Insulin; Intestines; Knowledge; Lead; Malignant Neoplasms; Midgut; Modeling; Molecular; Natural regeneration; Organ Size; Pathway interactions; Pattern; Play; Post-Translational Protein Processing; Regenerative Medicine; Regulation; Role; Signal Pathway; Signal Transduction; System; Therapeutic; Tissues; Tumor Suppressor Proteins; cancer cell; cancer therapy; cell growth; extracellular; hedgehog signal transduction; human disease; insight; medulloblastoma; novel; organ growth; organ regeneration; public health relevance; receptor; response; self-renewal; smoothened signaling pathway; stem; stem cell differentiation; stem cells; transcription factor

 DESCRIPTION (provided by applicant): Cell signaling plays a central role in embryonic development and adult tissue homeostasis and its deregulation can lead to human diseases such as cancer. Therefore, understanding how extracellular signals are integrated to control cell growth and patterning during development, and how they coordinate stem cell activity in tissue homeostasis is of central importance in biomedical research. Our overarching goal is to understand how signaling networks control organ development and regeneration, with an emphasis on Hedgehog (Hh) and Hippo (Hpo) 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 receptor-like molecule Smoothened (Smo) to the transcription factor Ci/Gli. However, the molecular mechanism underlying Hh signal transduction is not fully understood. In this study, we will investigate how Smo cell surface expression and activity are regulated by post-translational modifications (PTMs), and how Smo regulates the downstream signaling complexes to convert Ci/Gli from a repressor to an activator. The Hpo pathway is a newly identified tumor suppressor pathway that controls tissue growth and organ size by simultaneously regulating cell growth, proliferation, and apoptosis. Deregulation of Hpo pathway activity has also been implicated in many types of human cancer. Despite its central importance in development and diseases, the molecular mechanism underlying Hpo pathway regulation remains poorly understood. We have developed a genetic modifier screen allowing us to identify novel pathway regulators. We will extend the screen and investigate the mechanisms by which the identified new components regulate Hpo pathway activity. We also study the role of Hh, Hpo and other signaling pathways in adult tissue homeostasis and regeneration. Drosophila adult midgut has emerged as an attractive model to study how the self-renewal, proliferation and differentiation of stem cells are coordinated, not only because the cell lineage of the midgut is relatively simple and well defined, but also because conserved genetic pathways and regulatory mechanisms are utilized in this system. We have demonstrated that intestinal stem cells (ISCs) in the midgut can be activated in response to tissue damage induced by chemicals, and uncovered the role of multiple signaling pathways, including Insulin, Hpo, and Hh pathways, in the regulation of ISC activity during midgut regeneration. In addition, we have identified the epithelia-derived BMP as a niche signal for ISC self-renewal. In the proposed study, we will investigate how the niche signals are dynamically regulated and integrated to control ISC self-renewal, proliferation and differentiation. The knowledge gained from this study will have important implications for developmental biology, cancer biology and regenerative medicine.

 描述(申请人提供)：细胞信号在胚胎发育和成人组织动态平衡中起着核心作用，它的失控可能会导致人类疾病，如癌症。因此，在生物医学研究中，了解细胞外信号如何整合以控制细胞发育过程中的生长和模式，以及它们如何协调组织内稳态中的干细胞活动是至关重要的。我们的首要目标是了解信号网络如何控制器官的发育和再生，重点是Hedgehog(HH)和Hippo(Hpo)信号通路。从果蝇到人类，HH信号控制着许多关键的发育过程，它的异常活动与许多人类癌症有关，包括髓母细胞瘤和基底细胞癌。HH通过从受体样分子Smoothens(Smo)到转录因子Ci/Gli的保守信号级联起作用。然而，HH信号转导的分子机制尚不完全清楚。在这项研究中，我们将研究翻译后修饰(PTM)如何调节Smo细胞表面的表达和活性，以及Smo如何调节下游信号复合体，将Ci/Gli从抑制者转变为激活者。HPO途径是新近发现的一种肿瘤抑制途径，它通过同时调节细胞生长、增殖和凋亡来控制组织生长和器官大小。HPO途径活性的解除也被认为与许多类型的人类癌症有关。尽管它在发育和疾病中起着重要的作用，但HPO途径调控的分子机制仍然知之甚少。我们已经开发了一种遗传修饰物筛选，使我们能够识别新的途径调节因子。我们将扩大筛选范围，研究已发现的新成分调节HPO途径活性的机制。我们还研究了HH、HPO和其他信号通路在成人组织动态平衡和再生中的作用。果蝇成体中肠已成为研究干细胞如何自我更新、增殖和分化的一个有吸引力的模型。 协调，不仅是因为中肠的细胞谱系相对简单和明确， 还因为在这个系统中使用了保守的遗传途径和调节机制。我们已经证明了中肠中的肠干细胞(ISCs)可以在化学物质诱导的组织损伤中被激活，并揭示了包括胰岛素、Hpo和HH通路在内的多个信号通路在中肠再生过程中调节ISC活性的作用。此外，我们已经确定上皮源性BMP是ISC自我更新的利基信号。在这项拟议的研究中，我们将研究如何动态调节和整合生态位信号来控制ISC的自我更新、增殖和分化。从这项研究中获得的知识将对发育生物学、癌症生物学和再生医学具有重要意义。