Maternal Stress and Transmission of Asthma Risk

描述(由申请人提供)：本建议书描述了一项为期5年的培训计划，该计划将进一步发展首席研究员成为一名成熟的临床科学家，将他在儿科肺部医学方面的专业知识与作为独立研究员成功至关重要的新技能和经验结合起来。使用假说驱动和假说生成两种方法，这项建议将调查早期哮喘风险的潜在机制。母亲多次接触会增加子代患哮喘的风险，但其机制仍不明确。我的中心假设是，母亲的应激反应构成了一个共同的机械途径，通过这种途径，这些不同的暴露会增加子代对哮喘的易感性。需要测试的特定假设是，这种易感性是通过应激激素(皮质酮)依赖的途径介导的，该途径通过表观遗传(DNA甲基化)修饰改变新生儿/胎儿CD4细胞的功能。在具体目标1中，将进一步确定应激诱导的哮喘风险母体传播的小鼠模型，并确定应激激素的作用。在具体目标2中，新生儿CD4细胞的作用将通过检测Th2偏斜的细胞因子谱和过继地将幼稚的CD4细胞从哮喘易感新生儿转移到正常幼鼠来确定。在具体目标3中，将使用特定部位和全局发现方法来确定正常、哮喘和哮喘易感小鼠中这些细胞DNA甲基化的表观遗传学差异。最有希望的表观遗传标记子集将作为人类新生儿T细胞哮喘风险的生物标记进行测试。除了严格的实验计划外，该项目还包括免疫学、表观遗传学和生物信息学方面的结构化培训，使用课程作业、研讨会和专家咨询委员会的指导。经验丰富的赞助商详细介绍了职业技能和科学独立性发展的指导计划。专注的研究项目和严格的培训计划相结合，将使申请者作为一名独立的临床科学家取得成功，正如K08奖所设想的那样。相关性(见说明)：哮喘是一个主要的公共卫生问题。与父亲相比，母亲哮喘给后代带来的哮喘风险更大，母亲暴露在其他环境中也会增加易感性。这项研究将阐明新生儿哮喘风险的潜在机制，并将增加对哮喘发病机制的理解。它还将确定哮喘易感性的人类血液生物标记物，这可能会改善预防和治疗。

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program that will further develop the primary investigator as a full-fledged clinical scientist, combining his expertise in pediatric pulmonary medicine, with new skills and experience critical for success as independent investigator. Using both hypothesis-driven and hypothesis - generating approaches, this proposal will investigate mechanisms underlying asthma risk in early life. Multiple maternal exposures increase asthma risk in offspring, but the mechanisms remain uncharacterized. My central hypothesis is that maternal stress responses constitute a shared mechanistic pathway by which these various exposures induce increased asthma susceptibility in offspring. The specific postulate to be tested is that this susceptibility is mediated via a stress hormone (corticosterone) dependent pathway that alters neonatal/fetal CD4cell function through epigenetic (DNA methylation) modifications. In specific aim 1, a mouse model for stress-induced maternal transmission of asthma risk will be further characterized and the role of stress hormones determined. In specific aim 2, the role of neonatal CD4 cells will be determined by testing for a Th2-skewed cytokine profile and by adoptive transfer of naive CD4cells from asthma-susceptible neonates to normal pups. In the specific aim 3, epigenetic differences in DNA methylation of these cells in normal, asthmatic, and asthma-susceptible mice will be determined using site-specific and global discovery approaches. The most promising subset of epigenetic marks will be tested as biomarkers of asthma risk in human neonatal T cells. In addition to a rigorous experimental plan, the project includes structured training in immunology, epigenetics, and bioinformatics using coursework, seminars and guidance from an expert advisory committee. The experienced sponsor details a mentorship plan for development of career skills and scientific independence. The combination of a focused research project and rigorous training plan will allow the applicant to achieve a success as an independent clinical scientist, as envisioned by the K08 award. RELEVANCE (See instructions): Asthma is a major public health issue. Maternal asthma confers greater risk of asthma to offspring then does paternal, and other maternal exposures also increase susceptibility. This study will elucidate the underlying mechanisms for neonatal asthma risk and will add to the understanding of asthma pathogenesis. It will also identify human blood biomarkers for asthma susceptibility, which may improve prevention and therapy.