Genetic and hormonal mechanisms mediating sex differences in TB and TB-HIV
介导结核病和结核病艾滋病毒性别差异的遗传和激素机制
基本信息
- 批准号:10557906
- 负责人:
- 金额:$ 81.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:AbbreviationsAdoptive TransferAdrenal GlandsAndrogensAnimal ModelAnimalsAntitubercular AgentsBasic ScienceBiologicalBiological FactorsBone MarrowCellsCountryDisastersDoseEpidemicEpigenetic ProcessEstrogensEvaluationFOXP3 geneFemaleFour Core GenotypesGenesGeneticGenotypeGonadal Steroid HormonesGonadal structureGrowthHIVHIV InfectionsHIV/TBHealth Services AccessibilityHormonalHormonesHourHumanImmuneImmune responseImmunityImmunologicsInfectionInterferon Type IIInterleukin-4Knockout MiceLeukocytesLinkMacrophageMacrophage ActivationMediatingMethodsModelingMolecularMolecular AnalysisMusMycobacterium tuberculosisMycobacterium tuberculosis antigensNecrotic LesionObservational epidemiologyOutcomePathogenesisPatientsPeripheral Blood Mononuclear CellPersonsPlayPloidiesProcessProcessed GenesProliferatingResearch PersonnelResistanceRiskRoleSamplingSampling StudiesSelective Estrogen Receptor ModulatorsSeveritiesSex BiasSex ChromosomesSex DifferencesSignal TransductionT cell responseT-LymphocyteTLR7 geneTLR8 geneTNF geneTNFSF5 geneTestosteroneTuberculosisWhole BloodX ChromosomeX Inactivationcytokinedehydroepiandrosteronedesigngenetic analysishuman femalehuman maleimmune functionimmunoregulationmalemouse modelmultidisciplinaryneglectnovelpharmacologicresponsesextooltranscriptomicstuberculosis treatment
项目摘要
PROJECT SUMMARY
Tuberculosis (TB) occurs more frequently in males (~70% of cases) than females. While reduced access to care
for females and undercounting of female cases may contribute modestly to this longstanding epidemiologic
observation in some countries, both human studies (the Lűbeck disaster and eunuch studies) as well as animal
models underscore the fact that biological factors play a dominant role in female resistance to TB. Despite the
importance of this sex-bias in TB, it has gone largely neglected by basic science researchers. The central
scientific premise of this application is that defining the biological mechanisms of the male bias for TB will
enlighten our mechanistic understanding of TB pathogenesis and protective human immune responses in TB. A
multidisciplinary team with decades of expertise on sex differences (Klein), TB pathogenesis (Bishai), and sex
differences in HIV (Scully) will conduct the project.
This proposal will investigate the impact of genetics (X chromosome complement) and sex steroid hormones
on TB pathogenesis using cellular tools, animal models, and human samples. A key tool used in Aim 1 will be
the novel four core genotype (FCG) mouse model, in which animals with XX genotypes have male
gonads/hormone levels and those with XY genotypes have female gonads/hormone levels. This model will
enable us to differentiate the impact of genetics from those of the sex steroids on murine control of TB.
The X chromosome encodes numerous genes of immunologic importance including the genes that encode for
TLR7, TLR8, CYBB, NEMO, CD40L, and FOXP3. The process of X-chromosome inactivation (XCI)--in which
one female X chromosome is epigenetically silenced--is designed to provide balanced gene dosing between
females and males. Certain genes, however, can escape XCI, leading to a double gene dose in females. The
process of gene escape from XCI has not been studied in the context of TB, and advanced molecular tools will
be used in Aim 2 to investigate gene escape from XCI as a cause of the male bias in severity of TB.
While it is widely known that sex steroid signaling modulates immune function, the impact of sex steroids as a
basis for the male bias in TB has not been thoroughly investigated. Testosterone has an immunotolerizing effect,
reducing levels of IFN-γ and elevating levels of IL-4. In contrast, estrogen promotes higher levels of macrophage
activation and increases in TNF-α levels. In Aim 2, we will carefully dissect the role of sex steroids using adoptive
transfer methods as well as gonadectomized mice with selective hormone replacement.
Lastly, in Aim 3 we will extend these studies to assess the intersection of HIV infection, a critical risk for TB, and
sex differences in immunity. We will assess immune responses in samples from people living with HIV (PLWH)
on ART versus healthy controls (HCs), specifically balancing groups for sex. We will evaluate the ability of whole
blood and hMDM from PLWH and HCs to contain Mtb growth both alone and in the presence of DHEA. Lastly,
we will assess transcriptomic responses in PBMCs from male and female PLWH and HCs following Mtb infection.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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WILLIAM Ramses BISHAI其他文献
WILLIAM Ramses BISHAI的其他文献
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{{ truncateString('WILLIAM Ramses BISHAI', 18)}}的其他基金
Genetic and hormonal mechanisms mediating sex differences in TB and TB-HIV
介导结核病和结核病艾滋病毒性别差异的遗传和激素机制
- 批准号:
10484064 - 财政年份:2022
- 资助金额:
$ 81.38万 - 项目类别:
Microbiology, Immunology, Animal Modeling and Imaging
微生物学、免疫学、动物建模和成像
- 批准号:
10431023 - 财政年份:2022
- 资助金额:
$ 81.38万 - 项目类别:
Microbiology, Immunology, Animal Modeling and Imaging
微生物学、免疫学、动物建模和成像
- 批准号:
10593152 - 财政年份:2022
- 资助金额:
$ 81.38万 - 项目类别:
Targeted cell-depleting immunotherapy for TB and HIV
结核病和艾滋病毒的靶向细胞消耗免疫疗法
- 批准号:
10556322 - 财政年份:2020
- 资助金额:
$ 81.38万 - 项目类别:
Glutamine metabolism inhibitors for TB and TB-HIV: dual action as host-directed therapies with antibacterial activity
结核病和结核病艾滋病毒的谷氨酰胺代谢抑制剂:作为具有抗菌活性的宿主导向疗法的双重作用
- 批准号:
10686328 - 财政年份:2020
- 资助金额:
$ 81.38万 - 项目类别:
Targeted cell-depleting immunotherapy for TB and HIV
结核病和艾滋病毒的靶向细胞消耗免疫疗法
- 批准号:
10012368 - 财政年份:2020
- 资助金额:
$ 81.38万 - 项目类别:
Glutamine metabolism inhibitors for TB and TB-HIV: dual action as host-directed therapies with antibacterial activity
结核病和结核病艾滋病毒的谷氨酰胺代谢抑制剂:具有抗菌活性的宿主导向疗法的双重作用
- 批准号:
10456845 - 财政年份:2020
- 资助金额:
$ 81.38万 - 项目类别:
Targeted cell-depleting immunotherapy for TB and HIV
结核病和艾滋病毒的靶向细胞消耗免疫疗法
- 批准号:
10320031 - 财政年份:2020
- 资助金额:
$ 81.38万 - 项目类别:
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