Mathematical Modeling of Neurons and Endocrine Cells

神经元和内分泌细胞的数学模型

• 批准号: 10008647
• 负责人: Arthur Sherman
• 金额: $ 19.66万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10008647
• 关键词: Action Potentials; Anterior Pituitary Gland; Area; Blood Cells; Calcium; Calcium Channel; Cell Adhesion; Cells; Chemicals; Complement; Coupled; Data; Development; Differential Equation; Dimensions; Discontinuous Capillary; Drug Metabolic Detoxication; Endocrine; Endoplasmic Reticulum; Endothelial Cells; Enzymes; Exocytosis; Extracellular Matrix; Female; Functional disorder; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic Markers; Genomics; Gland; Heterogeneity; Hodgkin-Huxley model; Hormones; Hypothalamic structure; Insulin; Investigation; Ligands; Mediating; Mediator of activation protein; Membrane; Modeling; Molecular; National Institute of Child Health and Human Development; Natural regeneration; Nerve; Neuroglia; Neurons; Neurosecretory Systems; Neurotransmitters; Nobel Prize; Organelles; Paper; Physiology; Pituitary Gland; Population; Preparation; Proteins; Rattus; Role; Second Messenger Systems; Signaling Protein; Sister; Solid; Specificity; Stem cells; Structure; Structure of beta Cell of islet; System; Time; Tissues; Work; base; cell type; comparative; intercellular communication; interest; male; mathematical model; novel; pituitary gland development; postnatal; sexual dimorphism; tool; transcriptome; transcriptome sequencing

Together with the Stojilkovic lab and the Genomics core of NICHD, we have initiated a new direction in these studies, single-cell RNAseq analysis of gene expression in the anterior pituitary. This gland is composed of five hormone producing cell types, glia-like folliculostellate cells, and endothelial and blood cells comprising the pituitary sinusoidal capillary network. Some key lines of inquiry in pituitary physiology include three-dimensional organization tissue organization and intercellular communication among cells, development and regeneration of pituitary cells, and the heterogeneity and function of folliculostellate cells. Great efforts have been dedicated towards these aims, but many of the molecular underpinnings remain unknown. We have carried out the first single-cell transcriptome study of anterior pituitary cells. We profiled over 6700 freshly dispersed cells from postpubertal male and female rats. In addition to confirming known markers, our transcriptome analysis highlights many novel genetic markers contributing to pituitary cell type identity and sexual dimorphism. We provide for the first time an estimate of the percentage of folliculostellate cells, and we identify at least two main subtypes of this heterogeneous cell population. Our data support the hypothesis that folliculostellate cells provide structural support for the hormone producing cells, as they express many genes encoding detoxification enzymes. Our analysis of expression of developmental, stem cell/progenitor, and neuroendocrine markers suggests that folliculostellate and hormone producing cells are sister cells with a common origin. We also provide a detailed view of cell type-dependent expression of genes encoding extracellular matrix, cell adhesion, and endogenous ligand proteins, critical for the tridimensional organization of the anterior pituitary and the cross-talk between its constituent cells. We expect the marker genes identified for pituitary cell types will serve as a solid base for future investigations into pituitary structure, function, and pathophysiology, as well as for the study of postnatal pituitary development, regeneration, and reorganization. A paper is in press.

我们与 Stojilkovic 实验室和 NICHD 的基因组学核心一起，在这些研究中开创了一个新方向，即垂体前叶基因表达的单细胞 RNAseq 分析。 该腺体由五种产生激素的细胞类型、神经胶质样滤泡星状细胞以及构成垂体窦毛细血管网络的内皮细胞和血细胞组成。垂体生理学的一些关键研究领域包括三维组织组织和细胞间的细胞间通讯、垂体细胞的发育和再生以及滤泡细胞的异质性和功能。人们为这些目标付出了巨大的努力，但许多分子基础仍然未知。 我们开展了第一个垂体前叶细胞的单细胞转录组研究。我们对来自青春期后雄性和雌性大鼠的 6700 多个新鲜分散的细胞进行了分析。除了确认已知标记之外，我们的转录组分析还强调了许多有助于垂体细胞类型识别和性别二态性的新遗传标记。我们首次提供了滤泡星状细胞百分比的估计，并且我们确定了这种异质细胞群的至少两种主要亚型。我们的数据支持这样的假设：滤泡星状细胞为激素产生细胞提供结构支持，因为它们表达许多编码解毒酶的基因。我们对发育、干细胞/祖细胞和神经内分泌标记物表达的分析表明，卵泡细胞和激素产生细胞是具有共同起源的姐妹细胞。我们还提供了编码细胞外基质、细胞粘附和内源配体蛋白的基因的细胞类型依赖性表达的详细视图，这对于垂体前叶的三维组织及其组成细胞之间的串扰至关重要。 我们期望为垂体细胞类型鉴定的标记基因将为未来垂体结构、功能和病理生理学的研究以及出生后垂体发育、再生和重组的研究奠定坚实的基础。 一篇论文正在印刷中。