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.

项目概要/摘要 早产是美国婴儿死亡的主要原因，而这些婴儿的肺部发育不成熟 是一个主要原因。作为气体交换的器官，高效的肺功能对于生物的生存至关重要 新生。出生时，早产肺处于囊状发育阶段，与正常肺相比，处于不成熟状态。 成熟的成人肺。这些不成熟的肺部在出生时首先暴露于空气中的物质和微生物，并且 因此需要做好防御准备。树突状细胞 (DC) 在这种屏障防御和启动中发挥着关键作用 然而，我们对这些不成熟肺部中 DC 的了解是有限的。我的调查 新生肺部揭示了早期 DC 中以前未知的表型异质性 隔间。此外，这些新生肺 DC 亚群在转录上与它们的不同。 新生儿后期的对应物。我们的数据共同支持了这样的观点：囊状的直流隔室 阶段肺在表型和功能上与成人不同。这些观察导致我们 假设新生肺含有表型和功能异质的阶段特异性 肺 DC。这一假设将通过以下具体目标来解决： 目标 1：询问 囊状阶段肺 DC 的个体发育，目标 2：确定囊状阶段 DC 的功能。这两个 目标将与其他肺部发育阶段（包括成熟肺部）进行比较。这些目标 将阐明囊状阶段 DC 室的个体发育和功能，并揭示其 在新生儿肺部炎症中具有重要意义。拟议的研究将是第一个全面分析 出生时的肺 DC 室及其在炎症中的作用。