Regulation of cell signaling and developmental adaptation by sensory stimulation

通过感觉刺激调节细胞信号传导和发育适应

基本信息

批准号：
8916157
负责人：
Katja Brueckner
金额：
$ 30.91万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8916157
关键词：
Acetylcholine Activins Address Adhesions Animals Biological Blood Cell Count Blood Cells Calcium Cations Cell Proliferation Cells Chemicals Cholinergic Antagonists Clinical Communication Defect Development Disease Drosophila genus Drosophila melanogaster Environment Event Exposure to Failure Feedback Foundations Functional disorder Gated Ion Channel Genetic Genus Mentha Goals Health Hematopoietic Hematopoietic System Hemocytes Homeostasis Image Interruption Irritants Larva Life Ligands Light Link Malignant - descriptor Mediating Mediator of activation protein Membrane Menthol Mission Modeling Molecular Neurons Organ Painless Peripheral Nervous System Peripheral Nervous System Diseases Physiological Play Preparation Prevention strategy Production Proliferating Regulation Research Role Second Messenger Systems Sensory Signal Transduction Stem Cell Development Stereotyping Stimulus System Time Tissues Work allyl isothiocyanate animal tissue in vivo innovation loss of function nerve supply novel programs receptor relating to nervous system response second messenger sensory input sensory stimulus stem cell niche

项目摘要

DESCRIPTION (provided by applicant): Cell proliferation, survival and differentiation are commonly known to be regulated by stereotyped developmental programs and physiological feedback mechanisms. However, far less is understood how extrinsic sensory stimuli, through local innervation by the peripheral nervous system, modulate the signaling and responses of cells and tissues in the developmental adaptation and homeostasis of animal tissues. We address this question using a simple Drosophila melanogaster model of niche support by the PNS, focusing on the hematopoietic pockets (HPs) in the body wall of the optically transparent larva. In this system, blood cells (hemocytes) reside in direct physical contact with segmentally repeated sensory PNS clusters, functionally rely on the PNS for their localization and trophic survival, and are induced to proliferate in these microenvironments. We identified PNS neuron-produced Activin as a key regulator of hemocyte adhesion, localization and number, demonstrating that factors from the PNS determine hemocyte signaling and biological responses (Makhijani et al. in prep.). Examining the role of neuron excitation in the HPs, we find that transient silencing of PNS neuronal activity through inducible genetic systems or acetylcholine antagonists results in the rapid scattering or dispersal of resident hemocytes; conversely, PNS stimulants such as the irritant chemicals AITC (wasabi), menthol (mint), or blue light induce recruitment of blood cells to HPs and cause a rise in blood cell numbers over time. Exposure of intact living larvae to these noxious stimuli causes a rapid increase in intracellular calcium (Ca2+), both in PNS neurons and, subsequently, in hemocytes, consistent with an activation of Trp (Transient receptor potential) channels. We hypothesize that activation of the PNS by noxious stimuli regulates blood cell responses through the release or presentation of molecular factors; PNS signals promote hemocyte localization to HPs and facilitate exposure to inductive signals from the microenvironment, resulting in an adaptation of the animal's blood cell pool. The objective of the proposed research is to (1) Determine which aspects of blood cell development are regulated by PNS activity; (2) Identify an inducible mechanism how blood cells are activated by the PNS, focusing on Act and acetylcholine as candidate inducible signals; (3) Dissect the mechanistic sequence by which the irritant AITC (wasabi) regulates blood cell responses. This research is innovative, because we established this simple Drosophila model to study the role of the PNS in the support of a target tissue during development, and now propose to utilize the system to understand the signaling events and biological responses that are triggered in target cells following induction by extrinsic sensory stimuli. This work is significan because it is expected to reveal general principles of how the PNS and its afferent inputs regulate signaling in the homeostasis and developmental adaptation of animal tissues. Interruptions in this communication, such as in peripheral neuropathies, may be the cause of developmental defects and organ degeneration.

描述（由申请人提供）：众所周知，细胞增殖、存活和分化受到定型发育程序和生理反馈机制的调节。然而，人们对外在感觉刺激如何通过周围神经系统的局部神经支配，在动物组织的发育适应和稳态中调节细胞和组织的信号传导和反应知之甚少。我们使用由三七总皂甙支持的简单果蝇生态位模型来解决这个问题，重点关注光学透明幼虫体壁中的造血袋（HP）。在这个系统中，血细胞（血细胞）与分段重复的感觉三七总皂苷簇直接物理接触，功能上依赖于三七总皂苷的定位和营养生存，并在这些微环境中被诱导增殖。我们确定三七总皂苷神经元产生的激活素是血细胞粘附、定位和数量的关键调节剂，证明三七总皂苷的因子决定血细胞信号传导和生物反应（Makhijani 等人，准备中）。检查 HP 中神经元兴奋的作用，我们发现通过诱导遗传系统或乙酰胆碱拮抗剂短暂沉默 PNS 神经元活动会导致驻留血细胞快速分散或分散；相反，PNS 兴奋剂，如刺激性化学物质 AITC（芥末）、薄荷醇（薄荷）或蓝光，会诱导血细胞向 HP 募集，并导致血细胞数量随着时间的推移而增加。完整的活幼虫暴露于这些有害刺激会导致三七总皂苷神经元和随后的血细胞中的细胞内钙 (Ca2+) 快速增加，这与 Trp（瞬时受体电位）通道的激活一致。我们假设，有害刺激激活三七总皂苷，通过分子因子的释放或呈现来调节血细胞反应； PNS 信号促进血细胞定位到 HP，并促进暴露于来自微环境的感应信号，从而导致动物血细胞库的适应。本研究的目的是 (1) 确定血细胞发育的哪些方面受到三七总皂苷 (PNS) 活性的调节； (2) 确定三七总皂苷激活血细胞的诱导机制，重点关注 Act 和乙酰胆碱作为候选诱导信号； (3) 剖析刺激性 AITC（芥末）调节血细胞反应的机制序列。这项研究具有创新性，因为我们建立了这个简单的果蝇模型来研究三七总皂苷在发育过程中支持靶组织的作用，现在建议利用该系统来了解靶细胞中触发的信号事件和生物反应受到外在感觉刺激的诱导后。这项工作意义重大，因为它有望揭示三七总皂甙及其传入输入如何调节动物组织稳态和发育适应中信号传导的一般原理。这种交流的中断，例如周围神经病，可能是发育缺陷和器官退化的原因。