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Maturation of Normal & Sensitized Airway Contractility

正常成熟度

基本信息

批准号：
7571628
负责人：
THOMAS Miles MURPHY
金额：
$ 34.08万
依托单位：
DUKE UNIVERSITY
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：
2006-04-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7571628
关键词：
Address Adolescent Adult Affect Age Amino Acids Animal Model Antigens Asthma Beginning of Life Biological Models Birth Boxing Calcium Calmodulin Cavia Contractile Proteins Cyclic AMP-Dependent Protein Kinases Cytoskeleton Desmin Development Early treatment Experimental Designs Filament G-Protein-Coupled Receptors Generations Genetic Immune Inflammation Injection of therapeutic agent Inositol Intermediate Filament Proteins Intermediate Filaments Intervention Life Light Live Birth Measurement Mechanics Mediating Microscopic Modeling Muscle Muscle Cells Myosin Heavy Chains Myosin Light Chain Kinase Myosin Light Chains Neonatal Newborn Infant Oranges Ovalbumin Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Post-Transcriptional Regulation Prevalence Principal Investigator Property Protein Dephosphorylation Protein Isoforms Protein phosphatase Proteins Publications Regulation Research Personnel Resistance Role Signal Transduction Smooth Muscle Testing Vimentin airway hyperresponsiveness base early childhood fetal genetic regulatory protein human tissue inorganic phosphate myosin phosphatase neonate novel p21 activated kinase prevent programs receptor release of sequestered calcium ion into cytoplasm research study respiratory smooth muscle vimentin kinase

项目摘要

Asthma prevalence is greater during childhood and early airway insults may affect the expression of asthma in adults. Airway reactivity in several species increases from minimal during fetal life and birth to a substantial level in a few days to weeks. We have discovered key and parallel roles for the phosphorylation of myosin light chain (MLC20) by myosin light chain kinase (MLCK) and the reduced mechanical opposition to shortening in the normally augmented shortening of airway smooth muscle (ASM) in 3 week old juvenile guinea pigs and immune-augmented shortening in adults following neonatal sensitization. Maximal force generation is unchanged with maturation and following sensitization. Based on our results: ASM shortening declines from juveniles to adulthood while the internal resistance to shortening Rsi and the passive stiffness of the muscle increase. MLCK levels and the phosphorylation of MLC20 decline in parallel. In preliminary experiments neonatal sensitization increases ASM shortening and MLCK content and decreases the Rsi of ADULT ASM only. In this application, these findings are integrated into a novel hypothetical mechanism that relfects a NEW PARADIGM for augmented smooth muscle shortening in normal non-neonatal juveniles and in adults previously sensitized as neonates. This paradigm suggests that changes in the cytoskeleton matrix to facilitate shortening are of similar importance to those factors that facilitate the phosphorylation of myosin light chain. It also suggests that airway hyperresponsiveness may have its origins (and thus the need for intervention) early in life. The specific aims are: 1. To determine whether or not increased MLCK content plays a key regulatory role in the increased ASM shortening in normal juvenile trachealis and adults sensitized as newborns. To determine whether or not the increased content of the fast isoforms SM1B and SM2B of myosin heavy chain increases ASM shortening. 2. To determine the genetic and protein regulation of MLCK expression with development and following neonatal sensitization. 3. To determine whether the increased shortening in normal juvenile trachealis and in adults sensitized as newborns is associated with passive mechanical properties that reduce the internal resistance to shortening. To determine whether the content/phosphorylation of the intermediate filaments desmin and vimentin plays a role in the internal resistance to shortening of airway smooth muscle.

儿童期哮喘患病率较高，早期气道损伤可能影响哮喘的表达在成年人中。几个物种的气道反应性从胎儿期和出生时的最小值增加到出生后的最小值。在几天到几周的时间里，我们已经发现了磷酸化的关键和平行作用，肌球蛋白轻链激酶（MLCK）对肌球蛋白轻链（MLC 20）的抑制作用以及机械对抗的降低 3周龄青少年正常增强的气道平滑肌（ASM）缩短豚鼠和新生儿致敏后成人的免疫增强缩短。最大力世代不随成熟和致敏而改变。根据我们的研究结果：ASM缩短从青少年到成年期下降，而内部阻力缩短Rsi和被动刚度肌肉的增长。MLCK水平和MLC 20的磷酸化水平平行下降。初步实验新生儿敏化增加ASM缩短和MLCK含量，并降低仅适用于ADEASM。在本申请中，这些发现被整合到一个新的假设机制中，反映了正常非新生儿青少年平滑肌缩短增强的新范式，在之前作为新生儿致敏的成人中。这种模式表明，细胞骨架的变化基质促进缩短的因子与那些促进磷酸化的因子具有相似的重要性，肌球蛋白轻链它还表明，气道高反应性可能有其起源（因此，需要早期干预）。具体目标是：1.确定MLCK是否增加含量在正常幼年和成年人的ASM缩短增加中起关键调节作用像新生儿一样敏感。为了确定是否增加的快速亚型SM 1B和SM 1B的含量，肌球蛋白重链的SM 2B增加ASM缩短。2.为了确定遗传和蛋白质调节， MLCK表达与发育和新生儿致敏有关。3.以确定是否正常青少年气管和新生儿致敏成人气管缩短增加与被动机械性能，减少内部阻力缩短。以确定是否中间丝结蛋白和波形蛋白的含量/磷酸化在内部发挥作用对气道平滑肌缩短的抵抗力。