Sex hormones and innate immunity in tuberculosis
Sex hormones and innate immunity in tuberculosis
批准号:
10186699
负责人:
Maria Laura Gennaro
金额:
$19.61万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-06-08 至 2023-05-31
关键词:
AdultAntimycobacterial AgentsAppearanceAutologousBiologicalBlood specimenCause of DeathCellsChromatinClinicClinicalCommunicable DiseasesComplexDiseaseDisease susceptibilityEnrollmentEpidemiologyEpigenetic ProcessExhibitsFRAP1 geneFemaleGenderGonadal Steroid HormonesGrowthHealthHormonalHormonesHumanImmuneImmunologic MemoryIncidenceInfectionInfection ControlInterventionLinkLipidsLiteratureMemoryMetabolismMusMycobacterium tuberculosisNatural ImmunityOutcomePathogenesisPathway interactionsPlasmaPopulationPostpartum PeriodPredispositionPregnancyPregnant WomenProtein KinasePubertyReportingSamplingSerumSeveritiesSex BiasSex DifferencesSexual MaturationSignal TransductionSolidSpecialistStimulusTestingTimeTuberculosisUniversitiesVaccinationVariantWomanWorkantimicrobialcis-femalecis-maleepidemiology studyexperimental studygenome-widegenotypic sexhormonal contraceptionhormone therapyimmune functionimprovedin vivoinhibitor/antagonistmacrophagemalemenmonocytemortalitymycobacterialperipheral bloodrecruitresponsesexsexual dimorphismstemtransgendertransgender mentransgender womentuberculosis immunity
中文摘要
许多非传染性疾病和传染性疾病的发病率和严重程度以及接种疫苗的效力之间存在差异
英文摘要
Incidence and severity of many non-infectious and infectious diseases and vaccination efficacy differ between
men and women. Although these effects could reflect sex (the biological differences between male and female)
or gender (cultural norms associated with being male or female), a large body of evidence supports that these
differences have a biological component. Tuberculosis (TB), a bacterial infectious disease that is one of the top
ten causes of death worldwide, exhibits sex dimorphism. TB is more frequent and severe in men than women;
human and murine studies demonstrate a biological component of the epidemiologically observed sex
dimorphism. The present proposal stems from our surprising observation that human macrophages differentiated
from monocytes ex vivo in absence of autologous serum exhibit sex bias in M. tuberculosis infection control. Sex
bias was also observed in the accumulation of lipid droplets, a feature associated with decreased
antimycobacterial macrophage activity that is regulated by mechanistic target of rapamycin complex 1
(mTORC1) signaling. The present proposal will determine whether sex hormones determine control of M.
tuberculosis infection by inducing epigenetic reprogramming in monocytes/macrophages and involving mTORC1
signaling. The experimental plan stems from considerations derived from our preliminary results and the
literature. First, the absence of autologus serum, and therefore endogenous sex hormones, in the above-
mentioned experiments is consistent with the involvement of memory innate responses in the observed sex bias.
Second, memory innate responses, which protect against TB, are epigenetically regulated. Third, mTORC1
signaling is regulated by sex hormones and also epigenetically. The clinical capacity and expertise at Rutgers
University will provide access to populations that represent a diverse sex steroid hormone milieu: (a) cis-gender
women taking hormonal contraceptives and women enrolled during and after pregnancy at the Rutgers NJMS
OB/GYN clinic; and (b) transgender men and women at the Rutgers Center for Transgender Health. We have
articulated this proposal in two aims. We will leverage variations of plasma levels of sex steroid hormones due
to exogenous administration (Aim 1A) and pregnancy (Aim 1B) to determine relationships between hormonal
levels, epigenetic profiles in immune cells, and control of M. tuberculosis infection. In Aim 2, we will determine
whether the sex bias we observe in the macrophage control of M. tuberculosis infection is mTORC1-dependent.
The results of the proposed work will guide interventional strategies against TB with respect to sex, pregnancy,
and sex steroid hormonal therapy. Moreover, the fundamental and translational implications of the plan are
generalizable to sex bias in many other diseases.
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依托单位:
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COVID-19 Network of Networks Expanding Clinical and Translational approaches to Predict Severe Illness in Children (CONNECT to Predict SIck Children)
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批准号:10273971
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批准号:10733696
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资助金额:$152.48万
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Foam cells as drug targets in tuberculosis
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资助金额:$78.79万
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依托单位:
Foam cells as drug targets in tuberculosis
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批准号:10436308
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项目类别:
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资助金额:$78.71万
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财政年份:2019
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依托单位:
Biomarkers for tuberculosis: new questions, new tools
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批准号:8529930
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资助金额:$0.5万
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财政年份:2013
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负责人:Maria Laura Gennaro
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依托单位:
FISH-Flow platform for host-based tuberculosis diagnostics
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批准号:8895750
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项目类别:
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资助金额:$107.23万
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财政年份:2013
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负责人:Maria Laura Gennaro
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依托单位:
FISH-Flow platform for host-based tuberculosis diagnostics
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批准号:9319621
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项目类别:
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资助金额:$97.2万
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财政年份:2013
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负责人:Maria Laura Gennaro
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依托单位:
FISH-Flow platform for host-based tuberculosis diagnostics
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批准号:8474448
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项目类别:
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资助金额:$135.46万
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财政年份:2013
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负责人:Maria Laura Gennaro
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依托单位:
FISH-Flow platform for host-based tuberculosis diagnostics
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批准号:8721843
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资助金额:$112.33万
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财政年份:2013
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负责人:Maria Laura Gennaro
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依托单位:
Sigma factor networks of M. tuberculosis
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批准号:8717090
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项目类别:
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资助金额:$9.37万
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财政年份:2011
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负责人:Maria Laura Gennaro
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依托单位:
Sigma factor networks of M. tuberculosis
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批准号:8265612
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项目类别:
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资助金额:$10.32万
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财政年份:2011
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负责人:Maria Laura Gennaro
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依托单位:
Sigma factor networks of M. tuberculosis
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批准号:8174689
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项目类别:
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资助金额:$22.92万
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财政年份:2011
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负责人:Maria Laura Gennaro
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依托单位:
Immunodiagnosis of tuberculosis: new questions, new tools
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批准号:7481820
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项目类别:
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资助金额:$1.5万
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财政年份:2008
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负责人:Maria Laura Gennaro
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依托单位:
Proteome screening for tuberculosis outcome markers
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批准号:7084855
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项目类别:
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资助金额:$10.03万
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财政年份:2006
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依托单位:
Proteome screening for tuberculosis outcome markers
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批准号:7383005
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资助金额:$12.53万
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负责人:Maria Laura Gennaro
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依托单位:
Antibody profiles characteristic of tuberculosis state
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批准号:7383001
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资助金额:$11.67万
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负责人:Maria Laura Gennaro
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Proteome screening for tuberculosis outcome markers
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依托单位:
海外基金