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Cell signaling in development and regeneration

发育和再生中的细胞信号传导

基本信息

批准号：
10796720
负责人：
Jin Jiang
金额：
$ 14.2万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10796720
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

项目摘要

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信号传导共同作用，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。

项目成果

期刊论文数量（33）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of Gli ciliary localization and Hedgehog signaling by the PY-NLS/karyopherin-β2 nuclear import system.

PY-NLS/karyopherin-beta 2 核输入系统对 Gli 纤毛定位和 Hedgehog 信号传导的调节

DOI：
10.1371/journal.pbio.2002063
发表时间：
2017-08
期刊：
PLoS biology
影响因子：
9.8
作者：
Han Y;Xiong Y;Shi X;Wu J;Zhao Y;Jiang J
通讯作者：
Jiang J

SENP3 maintains the stability and function of regulatory T cells via BACH2 deSUMOylation.

SENP3 通过 BACH2 去SUMOylation 维持调节性 T 细胞的稳定性和功能

DOI：
10.1038/s41467-018-05676-6
发表时间：
2018-08-08
期刊：
Nature communications
影响因子：
16.6
作者：
Yu X;Lao Y;Teng XL;Li S;Zhou Y;Wang F;Guo X;Deng S;Chang Y;Wu X;Liu Z;Chen L;Lu LM;Cheng J;Li B;Su B;Jiang J;Li HB;Huang C;Yi J;Zou Q
通讯作者：
Zou Q

Ulk4 promotes Shh signaling by regulating Stk36 ciliary localization and Gli2 phosphorylation.