Maternal Stress and Transmission of Asthma Risk

母亲的压力和哮喘风险的传播

• 批准号: 7638687
• 负责人: ROBERT H. LIM
• 金额: $ 12.92万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-04 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7638687
• 关键词: 11-beta-Hydroxysteroid Dehydrogenases; Abbreviations; Adoptive Transfer; Advisory Committees; Air Pollution; Allergic; Allergic Contact Dermatitis; Asthma; Award; Bioinformatics; Biological Markers; Birth; Blood; Blood specimen; CD4 Positive T Lymphocytes; Carbenoxolone; Cells; Childhood; Clinical; Corticosterone; DNA Methylation; Data; Development; Development Plans; Dexamethasone; Diesel Exhaust; Dinitrochlorobenzene; Enzymes; Epigenetic Process; Glucocorticoid Receptor; Glucocorticoids; Hormones; Human; Hypersensitivity; Immune system; Immunology; In Vitro; Inflammation; Injection of therapeutic agent; Instruction; Interferon Type II; Interleukin-4; Life; Maternal Exposure; Measures; Mediating; Mentorship; Methylation; Modification; Mothers; Mus; Neonatal; Ovalbumin; Partner in relationship; Pathogenesis; Pathway interactions; Phenotype; Physiological; Predisposition; Pregnancy; Prevention therapy; Principal Investigator; Public Health; Pulmonology; Research Personnel; Research Project Grants; Risk; Role; Scientist; Site; Stress; Structure; T-Lymphocyte; Testing; Time; Toluene Diisocyanate; Training; Training Programs; Translating; Validation; acute stress; airway hyperresponsiveness; airway inflammation; base; biological adaptation to stress; bisulfite; career development; cytokine; experience; fetal; fetal blood; genome-wide; hypothalamic-pituitary-adrenal axis; improved; maternal stress; mouse model; neonatal human; neonate; offspring; particle; peripheral blood; pollutant; prevent; promoter; pup; receptor; response; restraint stress; skills; skin hypersensitivity; success; transmission process

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.

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，该计划将进一步培养主要研究者成为一名成熟的临床科学家，将其在儿科肺医学方面的专业知识与作为独立研究者取得成功至关重要的新技能和经验相结合。该提案将使用假设驱动和假设生成的方法，研究生命早期哮喘风险的机制。母亲多次暴露会增加后代的哮喘风险，但其机制仍不清楚。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，通过该途径，这些不同的暴露会导致后代哮喘易感性增加。要测试的具体假设是，这种易感性是通过应激激素（皮质酮）依赖性途径介导的，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，将进一步表征压力诱导的母亲传播哮喘风险的小鼠模型，并确定压力激素的作用。在具体目标 2 中，新生儿 CD4 细胞的作用将通过测试 Th2 倾斜的细胞因子谱以及将初始 CD4 细胞从哮喘易感新生儿过继转移到正常幼犬来确定。在具体目标 3 中，将使用位点特异性和全局发现方法来确定正常小鼠、哮喘小鼠和哮喘易感小鼠中这些细胞的 DNA 甲基化的表观遗传差异。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，该项目还包括利用课程作业、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。经验丰富的赞助商详细介绍了职业技能和科学独立性发展的指导计划。重点突出的研究项目和严格的培训计划相结合，将使申请人能够作为独立临床科学家取得成功，正如 K08 奖所设想的那样。相关性（参见说明）：哮喘是一个重大的公共卫生问题。与父亲相比，母亲哮喘会给后代带来更大的哮喘风险，而母亲的其他暴露也会增加易感性。这项研究将阐明新生儿哮喘风险的潜在机制，并将增进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。