Ontogeny and Function of Early-Life Pulmonary Dendritic Cells

早期肺树突状细胞的个体发育和功能

• 批准号: 10667996
• 负责人: Mark Bryan Headley
• 金额: $ 24.9万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667996
• 关键词: Acute Lung Injury; Address; Adoptive Transfer; Adult; Alveolar; Alveolar sac; Antibacterial Response; Antigens; Antiviral Response; Biological Assay; Birth; Bone Marrow; Cell Compartmentation; Cell Lineage; Cells; Cellular Assay; Communicable Diseases; Data; Dendritic Cells; Development; Disease; Exposure to; Fetus; First Births; Future; Gases; Gene Expression Profiling; Genetic; Genetic Transcription; Growth; Hematopoiesis; Heterogeneity; Immunity; Immunologic Surveillance; In Vitro; Infant Mortality; Infection; Inflammation; Investigation; Knowledge; Label; Lead; Life; Lung; Lung diseases; MHC Class II Genes; Macrophage; Maps; Marrow; Mediating; Microbe; Modeling; Mus; Nature; Neonatal; Newborn Infant; Organ; Ovum; Phenotype; Play; Population; Predisposition; Premature Birth; Pulmonary Inflammation; Research; Resolution; Role; Sorting; Source; Stimulus; System; T cell differentiation; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Toll-like receptors; Transgenic Organisms; United States; Vaccine Design; Viral; Viral Respiratory Tract Infection; Virus; XCR1 gene; cell motility; cell type; cytokine; detector; experimental study; fetal; insight; lung development; lung health; monocyte; mouse model; neonatal morbidity; neonatal period; novel vaccines; pathogen; premature lungs; progenitor; protein profiling; pulmonary function; response; single cell proteins; tool; transcriptome

PROJECT SUMMARY/ABSTRACT Premature birth is a leading cause of infant mortality in the United States, and lung immaturity in these babies is a major cause. As the organ of gas exchange, efficient lung function is critical for the survival of the newborn. At birth, premature lungs are in the saccular developmental stage, an immature state compared to the mature adult lungs. These immature lungs are first exposed to airborne material and microbes at birth, and thus need to be poised for defense. Dendritic cells (DC) play a key role in this barrier defense and initiating immunity, however, our understanding of DCs in these immature lungs is limited. My investigations into newborn lungs have revealed previously unknown phenotypic heterogeneity within the early-life DC compartment. Furthermore, these newborn lung DC subsets are transcriptionally distinct from their counterparts in later neonatal stages. Together our data support the idea that the DC compartment in saccular stage lungs is phenotypically and functionally distinct from the adult. These observations lead to our hypothesize that newborn lungs contain phenotypically and functionally heterogeneous stage-specific lung DCs. This hypothesis will be addressed through the following specific aims: Aim1: interrogate the ontogeny of saccular stage lung DCs, and Aim 2: Determine the functions of saccular stage DCs. Both of these aims will be performed in comparison to other lung development stages, including mature lungs. These aims will elucidate the saccular stage DC compartment in terms of ontogeny and function, and will reveal its significance in neonatal lung inflammation. The proposed research will be the first comprehensive analysis of the lung DC compartment at birth and its role in inflammation.

项目摘要/摘要 早产是美国婴儿死亡的主要原因，这些婴儿的肺部不成熟 是一个主要原因。作为气体交换的器官，有效的肺功能对于患者的生存至关重要。 新生儿在出生时，早产儿肺处于囊状发育阶段，这是一种不成熟的状态， 成熟的成人肺这些未成熟的肺在出生时首先暴露于空气中的物质和微生物， 因此需要做好防御的准备树突状细胞（DC）在这种屏障防御和启动免疫应答中起关键作用。 然而，尽管如此，我们对这些未成熟肺中的DC的理解是有限的。我调查的是 新生儿肺显示了早期DC中以前未知的表型异质性， 车厢此外，这些新生肺DC亚群在转录上与它们的 新生儿后期的对应物。我们的数据共同支持了这样的观点，即囊状细胞中的DC室 阶段的肺在表型和功能上与成人不同。这些观察导致我们 假设新生儿肺含有表型和功能异质性阶段特异性 肺DC。这一假设将通过以下具体目标加以解决： 目的2：确定肺囊状期DC的功能。这两 目的将与其他肺发育阶段（包括成熟肺）进行比较。这些目标 将阐明囊状阶段DC隔间的个体发育和功能，并将揭示其 在新生儿肺部炎症中的意义这项研究将是第一次全面分析 出生时的肺DC隔室及其在炎症中的作用。