Low-level toxicant perturbation of neural cell function

神经细胞功能的低水平毒物扰动

基本信息

批准号：
7050328
负责人：
MARK D NOBLE
金额：
$ 37.05万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2010-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This research is focused on understanding how non-catastrophic toxicant exposure disrupts normal development and function of the CNS. The continuing determination that concentrations of toxicants once thought to be safe are associated with a variety of maladies, combined with the large numbers of toxicants and potential toxicants found in our environment, make it of great importance to increase our understanding of how normal cellular function may be disrupted by such substances. A central goal of this effort is to identify general principles applicable to the understanding of large numbers of toxicants. The general principle/hypothesis that underlies this application, which emerges directly from our ongoing research, is that, regardless of its other activities, any toxicant that has pro-oxidant activity will have a highly predictable set of effects on both precursor cells and differentiated cells. These effects include inhibition of precursor cell division and enhancement of responsiveness to inducers of differentiation and cell death. This hypothesis, with its clear mechanistic predictions, allows the formulation of a general theory of developmental neurotoxicology applicable to exposure to a wide range of toxicants at concentrations that frequently occur in the environment. Moreover, the predictions of our hypothesis regarding the effects of low dose toxicant exposure on vulnerability to other potentially harmful agents may provide a new understanding of the reasons underlying the enormous variability seen in responsiveness of different individuals to putatively identical physiological stressors. Our in preliminary vitro experimentation provides strong support for the correctness of the hypothesis underlying this proposal, and has demonstrated marked effects of a variety of toxicants on neural cell function, including a striking enhancement of vulnerability to a variety of other physiological stressors. Biochemical analysis demonstrates that despite their different chemistries, all of the toxicants examined converge on Fyn and Cbl activation, leading to enhanced degradation of the PDGFRa. In sum, this research program will define the actions of sublethal concentrations of single toxicants on a variety of neural precursor cells, define the interactions of toxicants with other physiological stressors (including other toxicants) particularly in regards to synergistic toxicity reactions, will define cellular regulatory systems that are modulated by toxicant exposure, and will study clinically relevant situations in which toxicant load can enhance response to injury and in which follow on studies in human populations are both particularly important and comparatively straightforward to carry out.

描述（由申请人提供）：这项研究的重点是了解非胃毒性暴露如何破坏中枢神经系统的正常发育和功能。持续确定曾经被认为是安全的毒物浓度与各种疾病有关，再加上我们环境中发现的大量有毒物质和潜在的毒物，使我们非常重要地了解我们对这种物质可能如何破坏正常细胞功能的理解。这项工作的一个核心目标是确定适用于理解大量有毒物质的一般原则。基于该应用的一般原理/假设直接来自我们正在进行的研究，无论其其他活性如何，任何具有氧化活性的毒物都将对前体细胞和分化细胞都具有高度可预测的影响。这些影响包括抑制前体细胞分裂以及对分化和细胞死亡诱导者的反应性的增强。该假设及其明确的机理预测，允许制定一种适用于在环境中经常发生的浓度下暴露于广泛毒物的发育神经毒理学理论。此外，关于我们假设对低剂量有毒物质暴露对其他潜在有害药物脆弱性的影响的预测可能会提供对不同个体在反应性中对推杆相同生理压力源的巨大变异性的基本原因的新理解。我们在初步的体外实验为这一提案基于的假设的正确性提供了强烈的支持，并证明了各种毒物对神经细胞功能的显着影响，包括对其他各种生理压力源的脆弱性的显着增强。生化分析表明，尽管它们的化学成分不同，但所有有毒物质都在FYN和CBL激活上汇聚，从而导致PDGFRA的降解增强。总而言之，该研究计划将定义单一毒物对各种神经前体细胞的浓度的作用，定义毒性与其他生理压力源（包括其他毒物）的相互作用（包括其他有毒物质），尤其是在协同毒性反应方面，将在临床上造成的临床侵害，并将毒性造成的疾病加载，并将其定义为毒性的疾病，并在毒性中造成影响，并将其与毒性相关，从而使毒性接触到毒品，从而构成了毒性的影响，从而促进了毒品的影响，并将其与毒性相关，并将其与毒性相关，并将其与毒性相关，并将关于人类人群的研究特别重要，而且相对直接进行。