Role of Intracellular Calcium Release in Hedgehog Growth Factor Signaling

细胞内钙释放在刺猬生长因子信号传导中的作用

• 批准号: 8111137
• 负责人: DAVID J. GRUNWALD
• 金额: $ 17.94万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111137
• 关键词: Adopted; Affect; Basal cell carcinoma; Biochemical; Biological Assay; Calcium; Calcium Binding; Cell Differentiation process; Cells; Cognitive; Congenital Abnormality; Coupling; Defect; Development; Differentiation and Growth; Disease; Embryo; Embryonic Development; Erinaceidae; Event; Gene Expression; Gene Targeting; Genes; Growth Factor; Health; Human; Intestines; Ligands; Limb Development; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Modeling; Morphology; Muscle; Muscle Cells; Muscle Contraction; Muscle Development; Muscle Fibers; Muscle Weakness; Nervous system structure; Pathway interactions; Pattern; Process; Proteins; Regulation; Research Project Grants; Resources; Role; Ryanodine Receptor Calcium Release Channel; Shapes; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Solid; Somites; Spinal Ganglia; Surface; Testing; Tissues; Vertebrates; Zebrafish; adult stem cell; base; cancer type; cell growth; cell type; controlled release; ganglion cell; hedgehog signal transduction; high risk; mutant; nervous system development; notochord; novel; precursor cell; programs; public health relevance; release of sequestered calcium ion into cytoplasm; research study; response; smoothened signaling pathway; therapy development; trafficking; transcription factor; vertebrate hedgehog protein

DESCRIPTION (provided by applicant): Hedgehog (Hh) growth factor signaling is one of the principal pathways regulating tissue patterning in embryogenesis, best known in vertebrates for its essential roles in nervous system and limb development. Even modest perturbations in Hh signaling have been linked to developmental and cognitive defects in humans. Moreover, Hh also functions in regulating growth and differentiation of adult stem cells, so that defects in Hh pathway signaling have been causally linked to many types of cancers, including Basal Cell Carcinoma, and cancers of the pancreas, intestine, and nervous system. Understanding the requirements for and regulation of Hh signaling has important significance for the maintenance of human health and development of therapies. We have recently discovered an unexpected and previously undescribed requirement for the cellular response to Hh signaling. In the absence of normal function of the Ryanodine Receptor intracellular Calcium Release Channel (CRC), several cell types whose development is known to depend directly on Hh signaling in the zebrafish embryo fail to arise. In embryos deficient in CRC function, tissue precursor cells that normally sense and respond to Hh signals fail to upregulate genes, including patched, that are the earliest known markers of the Hh response pathway. As preliminary findings indicate that it is the responding cells that require CRC activity and that these cells do not die in the absence of CRC activity, we hypothesize that regulated calcium mobilization is required for cells to sense or to execute the response to the Hh growth factor. Because these findings are novel and are not anticipated by any prevailing model of Hh pathway function, and because the regulation of Hh pathway signaling is so important for human health, we seek to use the R21 Exploratory/Developmental Research Grant Program ("high risk - high impact") mechanism to further define the role of intracellular calcium mobilization in Hedgehog signaling. First, we will determine whether the requirement for CRC function is a general feature of the response to Hh signaling in the zebrafish embryo by measuring the effects of blocked CRC activity on the development of multiple Hh-dependent tissues. Second, we will determine whether Hh-signaling and/or Hh-receiving cells require CRC function. Third, we will begin to identify the specific role of calcium mobilization within the Hh signal transduction pathway. Results from these experiments will establish whether CRC activity is needed to transmit, receive, or respond to Hh signaling, and thus will form the basis of our future research directions. PUBLIC HEALTH RELEVANCE: Hedgehog (Hh) growth factor signaling is one of the principal intercellular signaling pathways controlling cell growth and differentiation. Defects in the regulation of Hh signaling contribute to both cancers and birth defects in humans. Understanding the requirements for and regulation of Hh signaling has important significance for the maintenance of human health and the development of disease therapies. This proposal investigates how the controlled release and mobilization of calcium within the cell contributes to the regulation of Hh signaling.

描述（由申请人提供）：刺猬（Hh）生长因子信号传导是胚胎发生中调节组织模式的主要途径之一，在脊椎动物中因其在神经系统和肢体发育中的重要作用而闻名。即使 Hh 信号传导的轻微扰动也与人类的发育和认知缺陷有关。此外，Hh 还具有调节成体干细胞生长和分化的功能，因此 Hh 通路信号传导缺陷与许多类型的癌症存在因果关系，包括基底细胞癌以及胰腺癌、肠癌和神经系统癌症。了解Hh信号传导的要求和调节对于维护人类健康和开发治疗方法具有重要意义。 我们最近发现了细胞对 Hh 信号反应的一个意想不到的、以前未描述过的要求。在缺乏 Ryanodine 受体细胞内钙释放通道 (CRC) 正常功能的情况下，斑马鱼胚胎中几种已知其发育直接依赖于 Hh 信号传导的细胞类型无法出现。在 CRC 功能缺陷的胚胎中，通常感知和响应 Hh 信号的组织前体细胞无法上调基因，包括 patched，这是 Hh 响应途径的最早已知标记。由于初步研究结果表明，反应细胞需要 CRC 活性，并且这些细胞在没有 CRC 活性的情况下不会死亡，因此我们假设细胞需要调节钙动员来感知或执行对 Hh 生长因子的反应。 由于这些发现是新颖的，并且是任何流行的 Hh 通路功能模型都没有预料到的，并且由于 Hh 通路信号传导的调节对人类健康非常重要，因此我们寻求使用 R21 探索性/发展研究资助计划（“高风险 - 高影响”）机制来进一步定义细胞内钙动员在 Hedgehog 信号传导中的作用。首先，我们将通过测量受阻的 CRC 活性对多种 Hh 依赖性组织发育的影响，确定 CRC 功能的要求是否是斑马鱼胚胎中对 Hh 信号传导反应的一般特征。其次，我们将确定 Hh 信号传导和/或 Hh 接收细胞是否需要 CRC 功能。第三，我们将开始确定钙动员在 Hh 信号转导途径中的具体作用。这些实验的结果将确定传输、接收或响应 Hh 信号是否需要 CRC 活动，从而构成我们未来研究方向的基础。 公共健康相关性：Hedgehog (Hh) 生长因子信号传导是控制细胞生长和分化的主要细胞间信号传导途径之一。 Hh 信号传导的调节缺陷会导致人类癌症和出生缺陷。了解Hh信号的需求和调控对于维护人类健康和疾病治疗的发展具有重要意义。该提案研究了细胞内钙的受控释放和动员如何有助于 Hh 信号传导的调节。