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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.

我们继续开展研究健康差异的生物学工作，因为健康的社会决定因素正是通过生物机制导致不同的健康结果。今年精选的值得注意的发现包括涉及表观遗传衰老、虚弱和细胞外囊泡作为疾病标志物以及凝溶胶蛋白作为代谢疾病标志物的研究。例如，我们在衰弱方面的工作仍然是多方面的。虚弱是一种临床综合征，被描述为生理储备减少和脆弱性增加。通常在老年人中进行检查，最近的研究表明，中年人会出现虚弱，并且与死亡率增加有关。我们扩展了对早期衰弱的研究，以进一步研究中年 HANDLS 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 的个体差异与虚弱状况和贫困水平有关。使用 CometChip 检测，我们评估了家庭收入高于和低于贫困的非虚弱和虚弱中年非裔美国人和白人的基线单链断裂和过氧化氢 (H2O2) 诱导的 DNA 氧化损伤和 DRC。对基线单链断裂的分析显示与虚弱、贫困、种族或性别没有关联。然而，我们发现在 H2O2 诱导的 DNA 氧化损伤中，虚弱和贫困之间存在相互作用。我们还确定了性与虚弱以及性与贫困状况与刚果民主共和国之间的相互作用。健康、贫困的社会决定因素与男性 DRC 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相关。 IL-10 水平与基线 DNA 损伤以及 H2O2 诱导的 DNA 损伤呈负相关，DRC 受 IL-4 水平和性别以及性别和贫困状况背景下 TNF-水平的影响。这是刚果民主共和国可能受到中年贫困状况影响的第一个证据。我们的数据表明，在检查与年龄相关的不同健康结果变得明显的生物学途径时，应考虑健康的社会决定因素。此外，我们还研究了 EV 中的线粒体 DNA (mtDNA) 和炎症蛋白是否可能在衰弱过程中充当损伤相关分子模式 (DAMP) 分子。为了确定 EV 及其相关 mtDNA 和炎症蛋白货物是否会因虚弱而改变，我们从全生命周期多元化社区健康老龄化 (HANDLS) 研究的非虚弱 (n = 90) 和虚弱 (n = 87) 中年 (45-55 岁) 参与者中分离出 EV。体弱的白人参与者中 EV 浓度最高。与非虚弱个体相比，虚弱个体的 EV mtDNA 水平显着更高。 EV 中六种炎症蛋白（FGF-21、HGF、IL-12B、PD-L1、PRDX3 和 STAMBP）的存在与虚弱显着相关。 EV炎症蛋白因虚弱状况、种族、性别和贫困状况而显着改变。值得注意的是，与体弱和非体弱的非洲裔美国参与者相比，体弱的白人参与者的 EV 相关 CD5、CD8A、CD244、CXCL1、CXCL6、CXCL11、LAP-TGF-β-1 和 MCP-4 水平较高。生活在贫困线以下的体弱白人参与者的 EV 相关 uPA 水平较高。 EV 相关的 CCL28 水平在非体弱女性中最高，CXCL1 在非体弱男性中最高。生活在贫困线以下的男性的 CD5、CD8A、CXCL1、LAP-TGF-beta-1 和 uPA 水平较高。生活在贫困线以上的个体的 CXCL6 水平显着较高。 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，EV 内的 mtDNA 可能在脆弱时充当 DAMP 分子。它与趋化因子和其他炎症 EV 货物蛋白的关联可能导致虚弱表型。此外，健康的社会决定因素贫困也会影响中年电动汽车的炎症物质。炎症相关代谢性疾病（2 型糖尿病）的日益流行，为提高我们对预防或更好地控制这种与年龄相关的疾病的潜在机制或生物标志物的理解提出了挑战。凝溶胶蛋白异构体作为细胞外肌动蛋白清除系统的一部分分泌到血浆中，该系统通过消化和去除受损细胞释放的肌动蛋白丝来发挥保护作用。最近的数据表明，血浆凝溶胶蛋白 (pGSN) 水平降低可作为炎症状况的生物标志物。细胞外囊泡 (EV) 是一组参与细胞间信号传导的细胞源性膜结构的异质组，与包括 2 型糖尿病在内的代谢和炎症疾病有关。我们检查了患有或不患有糖尿病的个体中 pGSN 水平是否与 EV 浓度和炎症血浆蛋白相关。我们对社会经济多样化的中年非裔美国人和白人研究参与者（患有或不患有糖尿病）的 pGSN 进行纵向量化（n = 104）。通过ELISA测定血浆凝溶胶蛋白水平。使用纳米颗粒跟踪分析测量 EV 浓度（子队列 n = 40）。在 SomaScan v4 蛋白质组平台上检测炎症血浆蛋白。男性的 pGSN 水平低于女性。与没有糖尿病的白人以及患有或不患有糖尿病的非裔美国人相比，患有糖尿病的白人的 pGSN 水平显着较低。对于生活在贫困线以下的成年人来说，患有糖尿病的人的 pGSN 水平低于没有糖尿病的人。无论糖尿病状况如何，生活在贫困线以上的成年人都有相似的 pGSN 水平。未发现 EV 浓度和 pGSN 水平之间存在相关性（r = - 0.03；p = 0.85）。大规模探索性血浆蛋白蛋白质组学揭示了 47 种蛋白质因糖尿病状态而存在显着差异，其中 19 种与 pGSN 水平显着相关，包括脂联素。在这个由患有和未患有糖尿病的不同种族个体组成的队列中，我们发现 pGSN 水平随糖尿病状况、性别、种族和贫困的不同而存在差异。我们还报告了 pGSN 与脂肪因子、脂联素和其他炎症和糖尿病相关蛋白的显着关联。这些数据提供了 pGSN 与糖尿病关系的机制见解。去年，我们在了解健康的社会决定因素与生物衰老之间的关系方面取得了进展。

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.