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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.

我们继续研究健康差异的生物学，因为健康的社会决定因素正是通过生物学机制导致不同的健康结果。今年的一些值得注意的发现包括研究表观遗传衰老、虚弱和作为疾病标志物的细胞外囊泡，以及作为代谢性疾病标志物的凝胶。

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.