Genomic signatures of inflammation: Pathways of racial discrimination, depressive symptoms, Vitamin D status with preterm birth among Black women

非西班牙裔黑人女性早产的可能性是后者的1.5倍(怀孕37周) 与非西班牙裔白人女性相比(14%比9%)。早产是新生儿的首要原因 黑人婴儿的发病率。怀孕的黑人女性也更有可能遭受种族歧视 和抑郁症状，有较高的维生素D缺乏风险[血浆25(OH)D浓度和lt；20 Ng/ml]与白人女性相比。种族歧视、抑郁症状和维生素D缺乏 与增加的促炎细胞因子(如肿瘤坏死因子-α、白介素6)有关，但研究没有 检测免疫相关基因的基因表达作为这些因子与肺结核的潜在途径。 外周单个核细胞(PBMC)含有淋巴细胞、单核细胞和树突状细胞，所有这些细胞都是 对免疫功能很重要，可以表达促炎和抗炎细胞因子。通过检查 外周血单核细胞在黑人孕妇队列中的基因表达模式，可以阐明 心理社会因素(例如种族歧视、抑郁症状)和 维生素D状态会增加患肺结核的风险。 使用来自168名怀孕的黑人妇女的数据，他们参与了Giurescu博士(Mentor)的R01研究，我将 检查种族歧视、抑郁症状、维生素D结合蛋白之间的关系 (VDBP)基因，血浆25(OH)D浓度，免疫细胞基因表达，系统性 炎症和出生时的胎龄(GA)。女性完成了问卷调查，并在8岁时抽血。 怀孕18周。问卷调查数据、血浆细胞因子(肿瘤坏死因子-α、IL-6、IL-8、IL-4、IL-10、干扰素-γ)水平和GA 出生时将从父母的研究中获得。冰冻的血浆和PBMC样本储存在Mentor‘s 实验室。血浆25(OH)D浓度将用液相色谱从冰冻样品中测量。 质谱学。VDBP基因将使用从细胞核中提取的DNA通过TaqMan分析进行评估 从外周血单核细胞中分离出来。在克劳斯博士(共同导师)的监督下，我将进行批量RNA测序 (RNA-seq)在冰冻PBMC上。我的目标是：(目的1)探索免疫细胞基因的差异表达 (1)肺结核妇女和足月分娩妇女；(2)维生素D缺乏妇女和妇女 维生素D充足；以及(目标2)检查种族歧视、抑郁 症状、血浆25(OH)D、VDBP基因、差异表达基因(在目标1中确定)，以及 全身性炎症与出生时的GA有关。建议的、严谨的培训计划和经验丰富的 导师团队将加快我成为独立调查员的速度，让我有时间学习尖端技术 利用基因组学和转录组学进行研究，培养组学分析和生物信息学方面的能力 数据，并获得团队领导技能。这项研究的结果将为NIH提供初步数据 R01研究确定肺结核的预测生物标记物。

Non-Hispanic Black women are 1.5 times more likely to have preterm birth (PTB; < 37 weeks gestation) compared with non-Hispanic White women (14% vs 9%). Preterm birth is the leading cause of neonatal morbidity among Black infants. Pregnant Black women are also more likely to experience racial discrimination and depressive symptoms and have higher risk for vitamin D deficiency [plasma 25(OH)D concentration <20 ng/ml] compared with White women. Racial discrimination, depressive symptoms and vitamin D deficiency have been associated with increased pro-inflammatory cytokines (e.g.,TNF-α, IL-6), but research has not examined the gene expression of immune-related genes as potential pathways of these factors with PTB. Peripheral mononuclear cells (PBMCs) contain lymphocytes, monocytes and dendritic cells all of which are important for immune function and can express both pro- and anti-inflammatory cytokines. By examining the gene expression pattern of PBMCs in a cohort of Black pregnant women, it could elucidate distinct or overlapping pathways by which psychosocial factors (e.g. racial discrimination, depressive symptoms) and vitamin D status increase risk for PTB. Using data from 168 pregnant Black women participating in Dr. Giurgescu's (mentor) R01 study, I will examine the associations among racial discrimination, depressive symptoms, Vitamin D Binding Protein (VDBP) genotype, plasma 25(OH)D concentration, gene expression of immune cell genes, systemic inflammation, and gestational age (GA) at birth. Women completed questionnaires and had blood drawn at 8- 18 weeks gestation. Questionnaire data, plasma cytokine (TNF-α, IL-6, IL-8, IL-4, IL-10, INF-γ) levels, and GA at birth will be available from the parent study. Frozen plasma and PBMC samples are stored in mentor's laboratory. Plasma 25(OH)D concentration will be measured from frozen samples using liquid chromatography/ mass spectrometry. VDBP genotype will be assessed by TaqMan assays using DNA extracted from nuclei isolated from PBMCs. Under the supervision of Dr. Kraus (co-mentor), I will conduct bulk RNA sequencing (RNA-seq) on frozen PBMCs. I aim to: (Aim 1) Explore differential gene expression of immune cell genes between (1) women with PTB and women with term birth; and (2) women with vitamin D deficiency and women with vitamin D sufficiency; and (Aim 2) Examine the pathways by which racial discrimination, depressive symptoms, plasma 25(OH)D, VDBP genotype, differentially expressed genes (identified in Aim 1), and systemic inflammation relate to GA at birth. The proposed, rigorous training plan and highly experienced mentorship team will accelerate my path to independent investigator, allowing me time to learn cutting-edge research using genomics and transcriptomics, develop competency in analysis and bioinformatics of omics data, and gain team leadership skills. The results from this study will provide the preliminary data for a NIH R01 study to identify predictive biomarkers for PTB.