Silica Nephropathy and Chronic Kidney Disease of Unknown Etiology
二氧化硅肾病和病因不明的慢性肾脏病
基本信息
- 批准号:10029114
- 负责人:
- 金额:$ 63.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-07 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Acute Renal Failure with Renal Papillary NecrosisAgrochemicalsAirAir PollutionAllopurinolAnimalsAreaBiopsyBurn injuryCell Culture TechniquesCell modelCellsCentral AmericaCharacteristicsChronicChronic Kidney FailureClinicalCommunicable DiseasesCountryDehydrationDepositionDiseaseDocumentationDoseElectron MicroscopyEpidemicEtiologyEvaluationExposure toFemaleHK2 geneHealthHeat Stress DisordersHeavy MetalsHistologicHumanHydration statusImageIndiaIndividualInductively Coupled Plasma Mass SpectrometryInflammasomeInhalationInjuryInjury to KidneyIntakeInterstitial NephritisKidneyKidney DiseasesLungMasksMass Spectrum AnalysisMediatingMesoamericanMethodsMexicoMicroscopyModelingMycophenolateNatureNephrologyOralOral IngestionOrganParticulate MatterPathologicPathologistPublic HealthRaman Spectrum AnalysisRattusReaction TimeRecordsRecurrenceReportingResearchRiceRiskRoleRouteSaccharumSafetySamplingSeasonsSilicic AcidSilicon DioxideSiteSri LankaTestingThailandTimeTissuesToxicologyTubular formationTubulointerstitial NephritisUrineagricultural regionamorphous silicatebaseclimate changedrinkingeffective therapyexposure routeglomerulosclerosishuman diseasekidney biopsymalemycophenolate mofetilnanoparticlenanosizednovelparticlepredictive testrespiratoryresponserural areatherapeutic evaluationtoxicantuptakexanthine oxidase inhibitor
项目摘要
Project Summary
Epidemics of chronic kidney disease of unknown etiology (CKDu) have emerged along the Pacific Coast
of Central America (Mesoamerican Nephropathy), in northern Sri Lanka (Sri Lankan nephropathy), in Andhra
Pradesh and other regions of India (Uddanam Nephropathy), and in Veracruz, Mexico. In all cases, the primary
histologic finding is chronic interstitial nephritis with variable degrees of glomerulosclerosis. To date a variety of
causes have been considered, including heavy metals, agrochemicals, infectious diseases, and recurrent heat
stress and dehydration. Here we evaluate the novel hypothesis that amorphous silica, released into the air during
the burning of sugarcane and rice, may be a primary cause. The evidence supporting this hypothesis consists
of the following: 1. Amorphous silica is present in sugarcane and rice and is released when sugarcane is burned
or rice husks are burned each season. 2. The particular matter fraction (PM2.5) of burned sugarcane and rice
contains 80-90 percent amorphous, nanoparticle sized silica. 3. Both PM2.5 and exposure to silica is associated
with risk for CKD, and records show that the amount of burning of sugarcane in Central America and of rice in
Sri Lanka parallel the epidemics in these countries. 4. Rats administered amorphous nanoparticle sized silica
develop CKD with minimal respiratory signs and the biopsies show chronic interstitial nephritis with silica particles
in tubules. 5. Human biopsies of subjects with Mesoamerican Nephropathy, Sri Lankan Nephropathy, and
Uddanam nephropathy show dramatic presence of amorphous nano-sized silica particles in tubules compared
to controls by darkfield spectral microscopy and confirmed by ICP-mass spectrometry of the kidney tissues.
Given these findings, we propose to 1) Identify the Route(s) and Mechanisms by which nanoparticle silica may
cause kidney injury in a rat model, evaluating both oral and intranasal approaches; varying the nanoparticle size,
and doing both a time and dose response; evaluating the potentially synergistic effect of heat; determining if the
mechanism involves lysosomal uptake and inflammasome activation; evaluating if other organs (such as the
lung) are involved, and testing the therapeutic potential of mycophenolate and allopurinol. 2) To characterize the
silica in the kidney biopsy tissue and urine using ICP-MS, Raman spectroscopy, electron microscopy and
enhanced darkfield hyperspectral imaging. 3) To identify the Impact of Silica Nephropathy in both Epidemic
CKDu and Other Renal Diseases by better characterizing silica nephropathy in kidney biopsies from known
epidemic areas, predicting and testing for silica nephropathy in other regions where sugarcane is burned (or
not); and 4) Evaluating previously collected kidney biopsies in Denver and Stockholm, and other areas of the
world to determine if silica is increased in CKDu compared to other renal diseases. These studies will
characterize silica nephropathy, possibly one of the first major kidney diseases associated with air pollution, and
with major implications for nephrology, public health, environmental safety, and human and animal health.
项目摘要
沿着太平洋沿岸出现了病因不明的慢性肾脏病(CKDu)流行病
中美洲(中美洲肾病),斯里兰卡北方(斯里兰卡肾病),安得拉邦
Pradesh和印度其他地区(Uddanam Nephropathy),以及墨西哥韦拉克鲁斯州。在所有情况下,
组织学表现为慢性间质性肾炎伴不同程度的肾小球硬化。去约会各种各样的
原因已被考虑,包括重金属,农用化学品,传染病,和经常性的热
压力和脱水在这里,我们评估新的假设,无定形二氧化硅,释放到空气中,
甘蔗和稻米的燃烧可能是主要原因。支持这一假设的证据包括
以下情况:1.无定形二氧化硅存在于甘蔗和大米中,当甘蔗燃烧时释放出来
或稻壳被烧掉。2.燃烧甘蔗和水稻的颗粒物组分(PM2.5)
含有80- 90%的无定形纳米颗粒大小的二氧化硅。3. PM2.5和暴露于二氧化硅都与
有记录显示,中美洲的甘蔗燃烧量和中美洲的大米燃烧量都有可能导致CKD。
斯里兰卡与这些国家的流行病类似。4.给予无定形纳米颗粒大小的二氧化硅的大鼠
发生CKD伴轻微呼吸体征,活检显示慢性间质性肾炎伴二氧化硅颗粒
在小管中。5.患有中美洲肾病、斯里兰卡肾病和
Uddanam肾病显示肾小管中显著存在无定形纳米级二氧化硅颗粒,
通过暗视野光谱显微镜观察并通过肾组织的ICP-质谱法确认。
鉴于这些发现,我们建议1)确定纳米二氧化硅可以
在大鼠模型中引起肾损伤,评价口服和鼻内方法;改变纳米颗粒大小,
并进行时间和剂量反应;评估热的潜在协同效应;确定
机制涉及溶酶体摄取和炎性体激活;评估是否有其他器官(例如
肺),并测试麦考酚酯和别嘌呤醇的治疗潜力。2)表征
使用ICP-MS、拉曼光谱、电子显微镜和
增强暗场超光谱成像。3)确定二氧化硅肾病在两种流行病中的影响
CKDu和其他肾脏疾病,通过更好地表征已知肾脏活检中的二氧化硅肾病
流行地区,预测和测试其他地区的二氧化硅肾病,其中甘蔗燃烧(或
4)评估先前在丹佛和斯德哥尔摩以及世界其他地区收集的肾活检标本。
以确定与其他肾脏疾病相比,CKDu中的二氧化硅是否增加。这些研究将
表征二氧化硅肾病,可能是与空气污染相关的第一种主要肾脏疾病,
这对肾病学、公共卫生、环境安全以及人类和动物健康具有重大意义。
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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Jared Michael Brown其他文献
Jared Michael Brown的其他文献
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{{ truncateString('Jared Michael Brown', 18)}}的其他基金
Silica Nephropathy and Chronic Kidney Disease of Unknown Etiology
二氧化硅肾病和病因不明的慢性肾脏病
- 批准号:
10461915 - 财政年份:2020
- 资助金额:
$ 63.54万 - 项目类别:
Silica Nephropathy and Chronic Kidney Disease of Unknown Etiology
二氧化硅肾病和病因不明的慢性肾脏病
- 批准号:
10682599 - 财政年份:2020
- 资助金额:
$ 63.54万 - 项目类别:
Silica Nephropathy and Chronic Kidney Disease of Unknown Etiology
二氧化硅肾病和病因不明的慢性肾脏病
- 批准号:
10212382 - 财政年份:2020
- 资助金额:
$ 63.54万 - 项目类别:
Nanoparticle-Protein Corona Structural Changes and Immunoreactivity
纳米颗粒-蛋白质电晕结构变化和免疫反应性
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8769110 - 财政年份:2014
- 资助金额:
$ 63.54万 - 项目类别:
Mechanisms of mast cell directed carbon nanotube toxicity
肥大细胞定向碳纳米管毒性机制
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8249077 - 财政年份:2010
- 资助金额:
$ 63.54万 - 项目类别:
Mechanisms of mast cell directed carbon nanotube toxicity
肥大细胞定向碳纳米管毒性机制
- 批准号:
9265096 - 财政年份:2010
- 资助金额:
$ 63.54万 - 项目类别:
Mechanisms of non-IgE Mast Cell Activation by Environmental Particulates
环境颗粒物激活非 IgE 肥大细胞的机制
- 批准号:
10424529 - 财政年份:2010
- 资助金额:
$ 63.54万 - 项目类别:
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