Maternal Stress and Transmission of Asthma Risk

描述（由申请人提供）：该提案描述了一个为期5年的培训计划，该计划将进一步发展首席研究员作为一个成熟的临床科学家，结合他在儿科肺部医学方面的专业知识，以及作为独立研究者成功的新技能和经验。采用假设驱动和假设生成两种方法，本提案将调查早期生活中哮喘风险的机制。母亲多次接触会增加后代患哮喘的风险，但机制尚不清楚。我的中心假设是，母亲的应激反应构成了一个共同的机制途径，通过这个途径，这些不同的暴露导致后代哮喘易感性增加。需要测试的具体假设是，这种易感性是通过应激激素（皮质酮）依赖途径介导的，该途径通过表观遗传（DNA甲基化）修饰改变新生儿/胎儿cd4细胞功能。在具体目标1中，将进一步表征应激诱导的母体哮喘风险传递的小鼠模型，并确定应激激素的作用。在特定目标2中，新生儿CD4细胞的作用将通过检测th2偏斜细胞因子谱和通过将哮喘易感新生儿的幼稚CD4细胞过代转移到正常幼犬中来确定。在特定的目标3中，这些细胞的DNA甲基化的表观遗传差异将使用位点特异性和全局发现方法来确定正常，哮喘和哮喘易感小鼠。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志物进行测试。除了严格的实验计划外，该项目还包括利用课程、研讨会和专家咨询委员会的指导进行免疫学、表观遗传学和生物信息学方面的结构化培训。经验丰富的赞助者详细介绍了一项指导计划，以发展职业技能和科学独立性。有针对性的研究项目和严格的培训计划相结合，将使申请人成为一名成功的独立临床科学家，正如K08奖所设想的那样。相关性（见说明）：哮喘是一个重大的公共卫生问题。与父亲相比，母亲的哮喘会给后代带来更大的哮喘风险，而其他母亲的暴露也会增加易感性。本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。它还将识别哮喘易感性的人类血液生物标志物，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.