Sensory and metabolic regulation of stem cell niche function

干细胞生态位功能的感觉和代谢调节

• 批准号: 9765702
• 负责人: E. Jane Albert Hubbard
• 金额: $ 37.84万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765702
• 关键词: Acute; Address; Affect; Afferent Neurons; Anatomy; Animals; Area; Behavior; Caenorhabditis elegans; Cells; Cues; Degenerative Disorder; Dependence; Development; Distal; Environment; Escherichia coli; Feeding behaviors; Fertility; Food; Genes; Genetic; Genetic Screening; Genetic Transcription; Germ Lines; Hermaphroditism; Homeostasis; Human; Image; Knowledge; Ligands; Link; Longevity; Maintenance; Malignant Neoplasms; Medical; Messenger RNA; Metabolic; Metabolism; Modeling; Molecular; Monitor; Neurons; Neurosecretory Systems; Notch Signaling Pathway; Nutrient; Organ; Organism; Pathway interactions; Physiological; Process; Production; Regenerative Medicine; Regulation; Reporter; Reproduction; Resolution; Role; Satiation; Sensory; Signal Transduction; Specificity; Stem cells; System; Testing; Thinness; Time; Tissues; Transforming Growth Factor beta; Work; cancer stem cell; cell behavior; critical period; dietary manipulation; food environment; food quality; germline stem cells; glucagon-like peptide 1; granulysin; human disease; microbial; mutant; neuroregulation; notch protein; prevent; receptor; reproductive; response; stem cell biology; stem cell niche; tool

The mechanisms by which food abundance modifies development and reproduction are not well understood. We identified a “neuron-to-niche” (TGFß-to-Notch) signaling mechanism in C. elegans that provides an unprecedented opportunity to determine how the food environment promotes the expansion of a stem cell pool during development. Specifically, we found that DAF-7/TGFß signaling from ASI neurons promotes the accumulation of germline stem cells during the period of development just prior to reproductive maturity. This regulation differs in fundamental ways from previously described roles for DAF-7/TGFß, including tissue- requirement for the TGFß receptor and downstream genetic dependencies. In the neuron-to- niche system, the TGFß receptor is required in the stem cell niche for the response to abundant food. There, the TGFß receptor pathway regulates the transcription of lag-2, a gene that encodes a ligand for the Notch receptor that is expressed in nearby germline stem cells. Notch activity in the germline stem cells prevents their differentiation and thereby facilitates their accumulation during development. Therefore, food – via neuronal TGFß – regulates the expression of a critical factor in the stem cell niche such that abundant food expands the germline stem cell pool. We will take advantage of the tools and features of C. elegans (including defined anatomy, sophisticated genetics, single-cell resolution, facile dietary manipulation, and live imaging), and the quantitative readout of lag-2 expression in the niche, to further elucidate the mechanistic underpinnings of this neuron-to-niche system. We will determine (i) the molecular mechanisms of TGFß signaling from the neurons that convey differences in food quantity, (ii) the quantitative relationship between neuronal TGFß and the niche lag-2 response, (iii) the role of sensory activity of the neuron (versus other neuromodulatory or metabolic inputs) (iv) the sensitivity and dynamics of the niche response to altered food abundance, and (v) the components of the microbial environment (sensory and/or nutritive) that regulate TGFß signaling-dependent lag-2 expression. The molecular pathways that work in this system are highly conserved and are implicated in stem cell biology and human disease states, especially cancer. Therefore, the project will advance basic scientific knowledge, with implications for many general medical areas, including fertility, cancer, and regenerative medicine.

食物丰富改变发育和繁殖的机制并不 很好理解。我们在C. 提供了一个前所未有的机会，以确定如何食品环境 在发育过程中促进干细胞库的扩增。具体来说，我们发现， ASI神经元的β 1 -7/TGF β 1信号促进生殖系干细胞的积累 在生殖成熟之前的发育期。这一规定的不同之处在于 从先前描述的β-7/TGF β的作用，包括组织- TGF β 1受体和下游遗传依赖性的需求。在神经元- 在干细胞生态位系统中，TGF β受体是干细胞生态位中所需的， 丰富的食物。在那里，TGF β受体途径调节lag-2的转录， 编码Notch受体的配体，Notch受体在附近的生殖系干细胞中表达。 生殖系干细胞中的Notch活性阻止它们的分化，从而促进它们的分化。 在发展过程中积累。因此，食物-通过神经元TGF β-调节 干细胞龛中关键因子的表达，使得丰富的食物扩大了干细胞龛。 生殖系干细胞库。我们将利用C语言的工具和特性。elegans （包括明确的解剖学，复杂的遗传学，单细胞分辨率，简单的饮食 操作，和实时成像），以及在小生境中的lag-2表达的定量读数， 以进一步阐明这种神经元-生态位系统的机制基础。我们将 确定（i）来自神经元的TGF β 1信号传导的分子机制， 食物量的差异，（ii）神经元TGF β 1和神经元TGF β 2之间的定量关系， 生态位滞后2响应，（iii）神经元感觉活动的作用（相对于其他 神经调节或代谢输入）（iv）生态位响应的敏感性和动力学 改变食物丰富度，以及（v）微生物环境的组成部分（感官 和/或营养性），其调节TGF β 1信号传导依赖性lag-2表达。分子 在该系统中起作用的途径是高度保守的，并且与干细胞生物学有关 和人类疾病状态，尤其是癌症。因此，该项目将推进基本 科学知识，对许多一般医学领域，包括生育， 癌症和再生医学