Roles of peripheral and central respiratory chemoreceptors in inbred rat strains

外周和中枢呼吸化学感受器在近交系大鼠品系中的作用

• 批准号: 7708739
• 负责人: Matthew Robert Hodges
• 金额: $ 9万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7708739
• 关键词: Acidosis; Acute; Address; Adult; Animals; Blood; Blood Gas Analysis; Blood gas; Brain; Brain Stem; Breathing; Cannulas; Carbon Dioxide; Carotid Body; Cell Nucleus; Characteristics; Chemoreceptors; Chronic; Cyanides; Dahl Hypertensive Rats; Data; Denervation; Disease; Environmental air flow; Future; Genetic; Genetic Determinism; Genomics; Glutamates; Goals; Homeostasis; Hypercapnia; Hypercapnic respiratory failure; Hypoxemia; Hypoxia; Immunohistochemistry; Implant; In Vitro; Inbred Strains Rats; Individual; Intracarotid; Investigation; Lead; Lesion; Maintenance; Measurement; Measures; Mentors; Microdialysis; Morphology; Neonatal; Neurons; Neurotransmitters; Normal Range; Norway; Nucleus solitarius; Oxygen; Pan Genus; Peripheral; Phase; Phenotype; Play; Plethysmography; Preparation; Principal Investigator; Rat Strains; Rattus; Rattus norvegicus; Recovery; Regulation; Relative (related person); Research Personnel; Respiratory Acidosis; Rest; Role; Site; Slice; Sodium; Staining method; Stains; Surface; Synaptic Transmission; Techniques; Testing; Tissues; Variant; Venous; biocytin; design; in vivo; insight; instrument; intravenous injection; neonate; patch clamp; pup; raphe nuclei; research study; respiratory; response; salt sensitive; sensory feedback

DESCRIPTION (provided by applicant): Acute adjustments in ventilation represent a powerful homeostatic mechanism for the maintenance of P02, PC02 and pH. Sensory feedback to the ventilatory control centers occurs via peripheral and central chemoreceptors, but here are several unresolved questions regarding the roles and relative importance of central chemoreceptors and their contributions to blood gas regulation during eupneic ventilation, and putative interactions peripheral chemoreceptors and central chemoreceptors. The overall goal of this proposal are to address questions regarding chemoreception by taking advantage of unique inbred rat strains with inherent, and large differences in C02 sensitivity; the Brown Norway (BN: low responder) and Dahl Salt-sensitive (SS: high responder) rat. First, I will determine if the deficit in C02 sensitivity in BN rats is due to decreased cellular C02/pH sensitivity of individual chemosensitive neurons in vitro, or numbers and/or altered morphology of chemosensitive neurons via immunohistochemistry. The hypothesis that central chemoreceptors play little role .in the regulation of eupneic PC02 and pH will be tested in the second aim by characterizing the effects of carotid body denervation in these strains. Last, there is evidence that the carotid chemoreceptors may directly regulate central C02 sensitivity. In the third aim, I will test this possibility using a combined in vivo and in vitro approach by first measuring the ventilatory response to focal acidosis in chemosensitive regions in adult BN and SS rats, and then by quantifying the cellular C02/pH sensitivity of individual central chemoreceptor neurons in vitro in BN and SS neonates before and after carotid body denervation. Applying these experimental techniques to these unique rat strains will provide significant insights into the relative roles and importance of peripheral and central chemoreception in eupneic ventilation, and their putative interaction. They will also provide insights into respiratory-related diseases, and will provide a framework for future genomic investigations aimed at identifying the genetic determinants, and therefore the unique cellular mechanisms by which central chemoreception occurs.

描述（由申请人提供）：通气的急剧调整代表了维持 P02、PCO2 和 pH 的强大体内平衡机制。通气控制中心的感觉反馈是通过外周和中枢化学感受器发生的，但这里有几个未解决的问题，涉及中枢化学感受器的作用和相对重要性及其在正常通气期间对血气调节的贡献，以及外周化学感受器和中枢化学感受器的假定相互作用。该提案的总体目标是通过利用具有固有的、在CO 2 敏感性方面存在巨大差异的独特近交系大鼠品系来解决有关化学感受的问题；挪威布朗（BN：低反应者）和达尔盐敏感（SS：高反应者）大鼠。首先，我将通过免疫组织化学确定BN大鼠中CO 2 敏感性的缺陷是否是由于体外单个化学敏感神经元的细胞CO 2 / pH敏感性降低，或化学敏感神经元的数量和/或形态改变所致。中枢化学感受器在正常 PC02 和 pH 的调节中起很小作用的假设将在第二个目标中通过表征这些菌株中颈动脉体去神经的影响进行检验。最后，有证据表明颈动脉化学感受器可以直接调节中枢CO 2 敏感性。在第三个目标中，我将通过首先测量局部通气反应，使用体内和体外相结合的方法来测试这种可能性。 成年 BN 和 SS 大鼠化学敏感区酸中毒，然后通过量化细胞 CO2/pH BN 和 SS 新生儿前后个别中枢化学感受器神经元的体外敏感性 颈动脉体去神经支配。将这些实验技术应用于这些独特的大鼠品系将为外周和中枢化学感受在平静通气中的相对作用和重要性以及它们假定的相互作用提供重要的见解。它们还将提供对呼吸系统相关疾病的见解，并将为未来的基因组研究提供一个框架，旨在确定遗传决定因素，从而确定中枢化学感受发生的独特细胞机制。