The Underlying Biology of Health Disparities

健康差异的根本生物学

基本信息

批准号：
10913093
负责人：
michele k evans
金额：
$ 77.42万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10913093
关键词：
Acceleration Actins Address Adult African American African American population Age Aging Appearance Automobile Driving Basic Science Behavioral Biological Biological Aging Biological Assay Biological Factors Biological Markers Biology CCL13 gene CXCL1 gene CXCL11 gene CXCL6 gene Cells Chronic Chronic Disease Clinical Clinical Research Cognition DNA DNA Damage DNA Repair Data Diabetes Mellitus Discrimination Disease Disease Marker Disease susceptibility Disparate Dissection Elderly Environmental Risk Factor Enzyme-Linked Immunosorbent Assay Epidemic Epigenetic Process Etiology FGF21 gene Gelsolin Gene Expression Genetic Goals Health Health Disparities Research Health Status Household Hydrogen Peroxide IL12B gene Income Individual Individual Differences Inflammation Inflammatory Interdisciplinary Study Interleukin-10 Interleukin-4 Laboratories Life Expectancy Link Longevity Measures Medical Metabolic Diseases Metabolic Marker Microfilaments Minority Mitochondrial DNA Molecular Morbidity - disease rate Neighborhoods Non-Insulin-Dependent Diabetes Mellitus Outcome Oxidative Stress Participant Pathway interactions Pattern Phenotype Physiological Plasma Plasma Proteins Population Poverty Predisposition Protein Isoforms Proteins Proteomics Psychosocial Factor Race Reporting Research Risk Role STAMBP gene Scientist Serum Severities Signal Transduction Socioeconomic Factors Structural Racism Structure Syndrome System TGFB1 gene TNF gene Time Translational Research Woman Work adipokines adiponectin age related brain health cell injury chemokine cohort cytokine disability epidemiology study extracellular extracellular vesicles fibroblast growth factor 21 frailty health disparity health outcome disparity healthy aging high risk improved insight intercellular communication literacy low socioeconomic status men middle age mortality nanoparticle nutrition oxidation population based prevent programmed cell death ligand 1 racial diversity sex social health determinants sociocultural determinant socioeconomics telomere

项目摘要

We have continued our work examining the biology of health disparities because it is through biological mechanisms that social determinants of health result in disparate health outcomes. Selected notable findings from this year include studies involving epigenetic aging, frailty, and extracellular vesicles as markers of disease and gelsolin as a marker of metabolic disease. For example, our work in frailty continues to be multifaceted. Frailty is a clinical syndrome described as reduced physiological reserve and increased vulnerability. Typically examined in older adults, recent work shows frailty occurs in middle-aged individuals and is associated with increased mortality. We have extended our work on early frailty to further examine the role of DNA oxidation damage related to inflammation and DNA repair capacity (DRC) among middle-aged HANDLS participants. We hypothesized that inter-individual differences in DNA oxidation damage and DRC are associated with frailty status and poverty level. Using the CometChip assay, we assessed baseline single-strand breaks and hydrogen peroxide (H2O2)-induced DNA oxidation damage and DRC in non-frail and frail middle-aged African American and White individuals with household incomes above and below poverty. Analysis of baseline single-strand breaks showed no associations with frailty, poverty, race, or sex. However, we identified an interaction between frailty and poverty in H2O2-induced DNA oxidation damage. We also identified interactions between sex and frailty as well as sex and poverty status with DRC. The social determinant of health, poverty, associates with DRC in men. Baseline DNA damage, H2O2-induced DNA damage as well as DRC were associated with serum cytokine levels. IL-10 levels were inversely associated with baseline DNA damage as well as H2O2-induced DNA damage, DRC was altered by IL-4 levels and sex, and by TNF- levels in the context of sex and poverty status. This is the first evidence that DRC may be influenced by poverty status at midlife. Our data show that social determinants of health should be considered in examining biological pathways through which disparate age-related health outcomes become manifest. In addition, we examined whether mitochondrial DNA (mtDNA) and inflammatory proteins in EVs may act as damage-associated molecular pattern (DAMP) molecules in frailty. To address whether EVs and their associated mtDNA and inflammatory protein cargo are altered with frailty, EVs were isolated from non-frail (n = 90) and frail (n = 87) middle-aged (45-55 years) participants from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. EV concentration was highest in frail White participants. EV mtDNA levels were significantly higher in frail individuals compared to non-frail individuals. The presence of six inflammatory proteins in EVs (FGF-21, HGF, IL-12B, PD-L1, PRDX3, and STAMBP) were significantly associated with frailty. EV inflammatory proteins were significantly altered by frailty status, race, sex, and poverty status. Notably, frail White participants had higher levels of EV-associated CD5, CD8A, CD244, CXCL1, CXCL6, CXCL11, LAP-TGF-beta-1 and MCP-4 compared to frail and non-frail African American participants. Frail White participants living below poverty had higher levels of EV-associated uPA. EV-associated CCL28 levels were highest in non-frail women and CXCL1 were highest in non-frail men. Men living below poverty had higher levels of CD5, CD8A, CXCL1, LAP-TGF-beta-1, and uPA. CXCL6 levels were significantly higher in individuals living above poverty. There was a significant correlation between EV mtDNA levels and the presence of inflammatory proteins. These data suggest that mtDNA within EVs may act as a DAMP molecule in frailty. Its association with chemokines and other inflammatory EV cargo proteins, may contribute to the frailty phenotype. In addition, the social determinant of health, poverty, influences the inflammatory cargo of EVs in midlife. The growing epidemic of the inflammation-related metabolic disease, type 2 diabetes mellitus, presents a challenge to improve our understanding of potential mechanisms or biomarkers to prevent or better control this age-associated disease. A gelsolin isoform is secreted into the plasma as part of the extracellular actin scavenger system which serves a protective role by digesting and removing actin filaments released from damaged cells. Recent data indicate a role for decreased plasma gelsolin (pGSN) levels as a biomarker of inflammatory conditions. Extracellular vesicles (EVs), a heterogeneous group of cell-derived membranous structures involved in intercellular signaling, have been implicated in metabolic and inflammatory diseases including type 2 diabetes mellitus. We examined whether pGSN levels were associated with EV concentration and inflammatory plasma proteins in individuals with or without diabetes. We quantified pGSN longitudinally (n = 104) in a socioeconomically diverse cohort of middle-aged African American and White study participants with and without diabetes mellitus. Plasma gelsolin levels were assayed by ELISA. EV concentration (sub-cohort n = 40) was measured using nanoparticle tracking analysis. Inflammatory plasma proteins were assayed on the SomaScan v4 proteomic platform. pGSN levels were lower in men than women. White individuals with diabetes had significantly lower levels of pGSN compared to White individuals without diabetes and to African American individuals either with or without diabetes. For adults living below poverty, those with diabetes had lower pGSN levels than those without diabetes. Adults living above poverty had similar pGSN levels regardless of diabetes status. No correlation between EV concentrations and pGSN levels was identified (r = - 0.03; p = 0.85). Large-scale exploratory plasma protein proteomics revealed 47 proteins that significantly differed by diabetes status, 19 of which significantly correlated with pGSN levels, including adiponectin. In this cohort of racially diverse individuals with and without diabetes, we found differences in pGSN levels with diabetes status, sex, race, and poverty. We also report significant associations of pGSN with the adipokine, adiponectin, and other inflammation- and diabetes-related proteins. These data provide mechanistic insights into the relationship of pGSN and diabetes. Our work on understanding the association of the social determinants of health with biologic aging progressed over the last year.

我们一直在研究研究健康差异的生物学，因为正是通过生物学机制，社会决定因素导致健康结果不同。今年以来所选的显着发现包括涉及表观遗传性衰老，脆弱和细胞外囊泡作为疾病和凝胶蛋白作为代谢疾病的标志的研究。例如，我们在脆弱中的工作继续是多方面的。脆弱是一种临床综合征，描述为减少生理储备和增加脆弱性。通常在老年人中检查的，最近的工作表明，中年个体发生脆弱，与死亡率增加有关。我们已经扩大了早期虚弱的工作，以进一步研究中年参与者中与炎症和DNA修复能力（DRC）相关的DNA氧化损伤的作用。我们假设DNA氧化损伤和DRC的个体差异与脆弱的状态和贫困水平有关。使用cometchip测定法，我们评估了基线单链断裂和过氧化氢（H2O2）诱导的DNA氧化损伤，而在非少女和脆弱的非裔美国人和白人人群中，贫困高于贫困和贫困的白人中的DNA氧化损伤和DRC。基线单链断裂的分析没有与脆弱，贫困，种族或性别的关联。但是，我们确定了H2O2诱导的DNA氧化损伤中脆弱与贫困之间的相互作用。我们还确定了性与脆弱之间的互动以及与刚果民主共和国的性别和贫困状况。健康的社会决定因素，贫穷，与刚果民主共同体的男人息息相关。基线DNA损伤，H2O2诱导的DNA损伤以及DRC与血清细胞因子水平有关。 IL-10水平与基线DNA损伤以及H2O2诱导的DNA损伤成反比，DRC随着性别和贫困状况而被IL-4水平和性别改变。这是第一个证据表明，刚果民主共和国可能受到中年贫困状况的影响。我们的数据表明，在检查生物学途径时应考虑健康的社会决定因素，通过这些途径，与年龄相关的健康结果变得明显。此外，我们检查了电动汽车中线粒体DNA（mtDNA）和炎症蛋白是否可以充当脆弱的损伤相关分子模式（DAMP）分子。为了解决电动汽车及其相关的mtDNA和炎症蛋白货物是否随着脆弱的形式改变，从非弗拉布（n = 90）和脆弱（n = 87）中年（45-55岁）的参与者中分离出EVS，来自整个生活范围（Handls）的多样性邻居中健康老龄化的参与者。 EV浓度在脆弱的白人参与者中最高。与非网络个体相比，脆弱的个体中的EV mtDNA水平明显更高。 EV中存在六种炎症蛋白（FGF-21，HGF，IL-12B，PD-L1，PRDX3和Stambp）与脆弱显着相关。脆弱的地位，种族，性别和贫困状况会显着改变EV炎性蛋白。值得注意的是，与非洲脆弱的非裔美国人相比，脆弱的白人参与者具有更高水平的EV相关CD5，CD8A，CXCL1，CXCL1，CXCL6，CXCL11，LAP-TGF-BETA-1和MCP-4。生活在贫困以下的脆弱的白人参与者具有更高水平的EV相关UPA。在非冻结女性中，与EV相关的CCL28水平最高，而CXCL1在非狂欢男性中最高。生活在贫困以下的男性具有更高水平的CD5，CD8A，CXCL1，LAP-TGF-BETA-1和UPA。生活在贫困上方的个体中的CXCL6水平明显更高。 EV mtDNA水平与炎症蛋白的存在之间存在显着相关性。这些数据表明，电动汽车内的mtDNA可能充当脆弱的潮湿分子。它与趋化因子和其他炎症性EV货物蛋白的关联可能有助于脆弱的表型。此外，贫困的社会决定因素会影响中年电动汽车的炎症货物。与炎症相关的代谢疾病的流行病已经日益增长的2型糖尿病梅洛蒂斯（Mellitus）提出了提高我们对潜在机制或生物标志物的理解，以防止或更好地控制这种与年龄相关的疾病。作为细胞外肌动蛋白清道夫系统的一部分，将凝胶素同工型分泌到血浆中，该系统通过消化和去除受损细胞释放的肌动蛋白丝发挥保护作用。最近的数据表明，血浆凝胶素（PGSN）水平降低是炎症条件的生物标志物的作用。细胞外囊泡（EV）是一组参与细胞间信号传导的细胞衍生的膜结构，与包括2型糖尿病的代谢性和炎症性疾病有关。我们检查了患有或患有糖尿病患者中的PGSN水平是否与EV浓度和炎症血浆蛋白有关。我们在有或没有糖尿病的中年非裔美国人和白人研究参与者中纵向量化PGSN（n = 104）。 ELISA测定了血浆凝胶素水平。使用纳米颗粒跟踪分析测量EV浓度（亚螺旋n = 40）。在Somascan V4蛋白质组学平台上测定了炎症性血浆蛋白。男性的PGSN水平低于女性。与没有糖尿病的白人相比，患有糖尿病的白人患有PGSN的水平明显降低，而患有或没有糖尿病的非洲裔美国人。对于生活在贫困以下的成年人，患有糖尿病的人的PGSN水平低于那些患有糖尿病的人。不管糖尿病状况如何，生活在贫困上方的成年人的PGSN水平相似。 EV浓度与PGSN水平之间没有相关性（r = -0.03； p = 0.85）。大规模的探索性血浆蛋白蛋白质组学揭示了47种蛋白质，这些蛋白质与糖尿病状态显着差异，其中19个与PGSN水平（包括脂联素）显着相关。在这种有或没有糖尿病的种族多样化的人群中，我们发现PGSN水平的糖尿病状况，性别，种族和贫困的差异。我们还报告了PGSN与脂肪因子，脂联素以及其他炎症和糖尿病相关蛋白的显着关联。这些数据为PGSN和糖尿病的关系提供了机械见解。我们了解健康的社会决定因素与生物衰老的关联的工作在去年进展。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sex-specific transcriptome differences in a middle-aged frailty cohort.

DOI：
10.1186/s12877-022-03326-7
发表时间：
2022-08-09
期刊：
BMC GERIATRICS
影响因子：
4.1
作者：
Pacheco, Natasha L.;Hooten, Nicole Noren;Zhang, Yongqing;Prince, Calais S.;Mode, Nicolle A.;Ezike, Ngozi;Becker, Kevin G.;Zonderman, Alan B.;Evans, Michele K.
通讯作者：
Evans, Michele K.

Age, sex, and race influence single-strand break repair capacity in a human population.

年龄、性别和种族影响人群的单链断裂修复能力。

DOI：
10.1016/j.freeradbiomed.2008.08.031
发表时间：
2008
期刊：
Free radical biology & medicine
影响因子：
7.4
作者：
Trzeciak,AndrzejR;Barnes,Janice;Ejiogu,Ngozi;Foster,Kamala;Brant,LarryJ;Zonderman,AlanB;Evans,MicheleK
通讯作者：
Evans,MicheleK

Oxidative damage to DNA and single strand break repair capacity: relationship to other measures of oxidative stress in a population cohort.

DOI：
10.1016/j.mrfmmm.2012.01.002
发表时间：
2012-08-01
期刊：
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
影响因子：
2.3
作者：
Trzeciak, Andrzej R.;Mohanty, Joy G.;Jacob, Kimberly D.;Barnes, Janice;Ejiogu, Ngozi;Lohani, Althaf;Zonderman, Alan B.;Rifkind, Joseph M.;Evans, Michele K.
通讯作者：
Evans, Michele K.

CRP Stimulates GDF15 Expression in Endothelial Cells through p53.