The Impact of Obesity and Leptin on the Development of Immune System Dysfunction and Hypertension in Females with Systemic Lupus Erythematous
The Impact of Obesity and Leptin on the Development of Immune System Dysfunction and Hypertension in Females with Systemic Lupus Erythematous
批准号:
10714532
负责人:
Erin Bassford Taylor
金额:
$31.54万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-01 至 2028-08-31
关键词:
Adipose tissueAdrenergic ReceptorAffectAmericanAppetite RegulationAutoantibodiesAutoimmuneAutoimmune DiseasesAutoimmunityAwarenessB-LymphocytesBlood PressureBody mass indexBone MarrowBrainCD4 Positive T LymphocytesCardiovascular DiseasesCellsCentral obesityChronicClinical DataControl AnimalDataDepositionDevelopmentDietDiseaseDisease ProgressionEnergy MetabolismExhibitsFatty acid glycerol estersFemaleFlow CytometryFunctional disorderGoalsHematopoieticHigh Fat DietHomeostasisHypertensionHypothalamic structureImmuneImmune System DiseasesImmune systemImmunoglobulin GImmunoglobulin MIn VitroInflammationInflammatoryInterventionKidneyKnowledgeLaboratoriesLeadLeptinLoxP-flanked alleleLupusMediatingModelingMorbidity - disease rateMusNormal RangeObesityOperative Surgical ProceduresOverweightPathogenesisPathogenicityPatientsPeripheralPopulationPristaneProductionPublishingRiskRoleRuralSelf ToleranceSignal PathwaySignal TransductionSympathetic Nervous SystemSystemic Lupus ErythematosusT cell infiltrationT-LymphocyteTechniquesTestingTissuesVisceralWomanadipokinesantagonistanti-dsDNA autoantibodyautoreactive B cellautoreactivityclinically relevantcomparison controleosinophilhypertensiveimmune functionimprovedin vivoinsightleptin receptormortalitynestin proteinpatient populationpharmacologictreatment effect
中文摘要
项目总结/文摘
英文摘要
PROJECT SUMMARY/ABSTRACT
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that primarily affects women and
is characterized by a loss of self-tolerance and expansion of autoreactive B and T lymphocytes, leading to the
production of autoantibodies. The autoantibody production leads to chronic inflammation, resulting in high rates
of hypertension and cardiovascular disease. Clinical data indicate that rates of obesity are increased in patients
with SLE, and even in the absence of an overweight or obese BMI, patients with SLE have altered fat deposition
and increased visceral adiposity compared to BMI-matched controls. SLE patients also have elevated circulating
levels of the adipokine leptin, including those patients with a BMI in the normal range. The central goal of this
project is to examine the pathogenic role of obesity and leptin in the development and progression of
SLE disease and the development of hypertension. To accomplish this goal, two clinically relevant models
of SLE, the female NZBWF1 mouse and the pristane-inducible model, will be utilized. Both models develop
hypertension as the disease progresses, and the NZBWF1 mouse exhibits obesity and hyperleptinemia on a
normal chow diet. In aim 1 we will use the NZBWF1 mouse to test the hypothesis that increased visceral
adiposity in SLE exacerbates disease progression and the development of hypertension via pathogenic immune
cells in adipose tissue. We will use surgical and pharmacological techniques to deplete adipose tissue or specific
immune cell populations within the adipose, and then assess the effect of these treatments on SLE disease
progression and the development of hypertension. Published and preliminary data indicate that leptin has effects
on the immune system via both direct effects on immune cells, and indirectly via signaling in the brain. To assess
the role of leptin in SLE disease progression by directly affecting immune cells, aim 2 will utilize the pristane-
inducible model of SLE and test the hypothesis that elevated leptin during SLE promotes disease progression
via direct effects on B and T lymphocytes in peripheral tissues. We will generate mice that lack leptin receptors
on B or T lymphocytes and induce SLE using pristane. In aim 3, we will test the hypothesis that leptin promotes
SLE disease via its actions in the CNS. First, we will induce lupus using pristane in mice that lack leptin receptors
in the CNS (Nestin-Cre x LepRflox/flox). We will also test whether the effects of leptin on autoimmune disease
progression are mediated by the sympathetic nervous system by utilizing adrenergic receptor blockade.
Together, the proposed studies will provide insight into distinct mechanisms whereby obesity and adipokine
dysregulation lead to immune system dysfunction and the development of hypertension in SLE.
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会议论文
Immune system dysfunction and gut dysbiosis in the pathogenesis of vascular dysfunction in autoimmunity
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批准号:10544784
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项目类别:
-
资助金额:$24.9万
-
财政年份:2022
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负责人:Erin Bassford Taylor
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依托单位:
Immune system dysfunction and gut dysbiosis in the pathogenesis of vascular dysfunction in autoimmunity
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批准号:10516456
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项目类别:
-
资助金额:$24.9万
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财政年份:2022
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负责人:Erin Bassford Taylor
-
依托单位:
Immune system dysfunction and gut dysbiosis in the pathogenesis of vascular dysfunction in autoimmunity
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批准号:9892176
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项目类别:
-
资助金额:$10.15万
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财政年份:2020
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负责人:Erin Bassford Taylor
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依托单位:
Mississippi Diversity in Hypertension and Cardiorenal Research Program
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批准号:10391332
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项目类别:
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资助金额:$0.0万
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财政年份:2014
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负责人:Erin Bassford Taylor
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依托单位:
Mississippi Diversity in Hypertension and Cardiorenal Research Program
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批准号:10663116
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项目类别:
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资助金额:$8.94万
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财政年份:2014
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负责人:Erin Bassford Taylor
-
依托单位:
The role of leptin in autoimmune-associated hypertension
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批准号:10403636
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项目类别:
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资助金额:$25.68万
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财政年份:2013
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负责人:Erin Bassford Taylor
-
依托单位:
The role of leptin in autoimmune-associated hypertension
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批准号:10159926
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项目类别:
-
资助金额:$25.68万
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财政年份:2013
-
负责人:Erin Bassford Taylor
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依托单位:
海外基金