Genomic determinants of bronchopulmonary dysplasia development in humans and an animal model

项目摘要。 这个指导以患者为导向的研究职业发展奖（K23）的目的是提供阿尔瓦罗 Moreira，医学博士，理学硕士，圣安东尼奥德克萨斯大学健康科学中心助理教授， 发展成为一名独立的学术医生科学家所必需的知识和技能。他的长期职业生涯 目的是了解与支气管肺炎发展相关的病理过程 发育不良（BPD）是早产儿中发病率和死亡率较高的疾病。为此，莫雷拉博士 结合使用高保真技术来验证两个基因组签名（n=20个基因）， 指导团队已经确定为BPD易感性的强预测因子。为了实现这一目标，莫雷拉博士和 他的指导小组设计了一个全面的计划，其基础是：（1）深入的基因组学实践培训 和生物信息学;（2）先进免疫学的教学和经验指导，以及（3）严格的培训， 临床试验该平台将为Moreira博士提供获得技能，知识和经验的基础 需要制定和测试尖锐的假设，将支持新生儿肺部疾病的进展。新生儿 被诊断患有BPD的患者发生全身性（失明，智力缺陷）和部位特异性 并发症（哮喘、复发性呼吸道感染、肺动脉高压）。BPD的特征在于 继发于慢性高氧暴露和呼吸机诱导损伤的异常肺发育。尽管 随着新生儿医学的进步，目前的治疗方法有限，而且大多无效。因此， 采取新的策略来减轻和预防BPD。在理解基本机制方面存在重大差距 在BPD中，归因于操作定义、缺乏强有力的新生组织生物储存库以及动物 这些模型不能概括人类生理学的复杂性。翻译基因组学具有重要意义 承诺作为克服这些障碍的一种方法。事实上，在一个120名早产儿的发现队列中， Moreira和他的指导团队已经确定了预测BPD并对BPD进行分层的基因组特征 在新生儿生命的前5天进行内型分析。在这个修订后的应用程序中，Moreira博士计划验证两个基因组 在一个大型的前瞻性早产新生儿队列（第1年，第2年）的签名。在第三年，他将测试一个 定制的基因组阵列，根据他的签名，以提供快速和可靠的BPD风险分层。 此外，Moreira博士的研究将评估FDA批准的生物制剂在以下疾病中的安全性和有效性： 一种模拟BPD的大型动物模型。这种单克隆抗体靶向一个可改变的过程， 在他的发现队列的基因组图谱中高度预测BPD。Moreira博士的K23研究将产生 一个丰富的学习和教育框架，直接告知他未来的R 01提案，旨在初级预防 BPD的战略。

PROJECT SUMMARY . The purpose of this Mentored Patient-Oriented Research Career Development Award (K23) is to provide Alvaro Moreira, MD, MSc, Assistant Professor at the University of Texas Health Science Center at San Antonio with the knowledge and skills requisite to develop into an independent academic physician scientist. His long-term career goal is to understand the pathologic processes that correlate with the development of bronchopulmonary dysplasia (BPD), a disease with high morbidity and mortality in premature neonates. To this avail, Dr. Moreira is incorporating the use of high-fidelity technology to validate two genomic signatures (n=20 genes) that he and his mentoring team have identified as strong predictors for BPD susceptibility. To achieve this goal, Dr. Moreira and his mentoring team have devised a comprehensive plan based on: (1) an in-depth hands on training in genomics and bioinformatics; (2) didactic and experiential instruction in advanced immunology, and (3) rigorous training in clinical trials. This platform will provide the basis for Dr. Moreira to gain the skills, knowledge and experience needed to formulate and test incisive hypotheses that will bolster advances in neonatal lung disease. Neonates diagnosed with BPD are at increased risk for systemic (blindness, mental deficiency) and site-specific complications (asthma, recurrent respiratory infections, pulmonary hypertension). BPD is characterized by an aberrant lung development secondary to chronic exposure to hyperoxia and ventilator-induced injury. Despite advances in neonatal medicine, current therapies are limited and largely ineffective. Thus, there is an urgency to adopt novel tactics to mitigate and prevent BPD. Significant gaps in understanding the underlying mechanisms in BPD are attributed to an operational definition, a lack of robust neonatal tissue biorepositories, and animal models that do not recapitulate the intricacies of human physiology. Translational genomics holds significant promise as an approach to overcome these barriers. Indeed, in a discovery cohort of 120 preterm neonates, Dr. Moreira and his mentoring team have identified genomic signatures that predict BPD and stratifies BPD endotypes in a neonate's first 5 days of life. In this revised application Dr. Moreira plans to validate two genomic signatures in a large prospective preterm neonatal cohort (Year 1, 2). In Year 3, he will test the ability of a customized genomic array, based on his signatures, to provide a quick and reliable BPD risk stratification. Furthermore, Dr. Moreira's studies will evaluate the safety and efficacy of an FDA-approved biologic in a one of a kind large animal model mimicking BPD. This monoclonal antibody targets a modifiable process found to be highly predictive for BPD in his genomic profile from the discovery cohort. Dr. Moreira's K23 studies will produce a rich learning and educational framework directly informing his future R01 proposal aimed at primary prevention strategies for BPD.