Regulation of Autoimmune Type 1 Diabetes by Serpins B1 and A1 (Alpha 1-Antitrypsin)
Serpins B1 和 A1(α 1-抗胰蛋白酶)对自身免疫性 1 型糖尿病的调节
基本信息
- 批准号:9556000
- 负责人:
- 金额:$ 21.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-17 至 2020-08-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnimalsAnti-Inflammatory AgentsAnti-inflammatoryAntibodiesAntibody titer measurementApoptoticAtlasesAutoimmune DiseasesAutoimmune ProcessAutoimmune ResponsesB Cell ProliferationBeta CellBiologicalBiological ProductsBlood GlucoseCell physiologyCellsCellular ImmunityCellular biologyClinicalClinical ResearchClinical TrialsCombined Modality TherapyComplementCoupledDataDiabetes MellitusDiseaseDuct (organ) structureDuctalDuctal Epithelial CellEconomic BurdenElastasesEnvironmental Risk FactorEpitheliumFinancial compensationFutureGeneticGlycosylated hemoglobin AGrowthHealthHealth Care CostsHealth ExpendituresHumanHyperglycemiaImmune responseIn VitroInbred NOD MiceInflammationInflammatoryInsulinInsulin ResistanceInsulin-Dependent Diabetes MellitusInterleukin-1 betaIslet CellIslets of LangerhansLaboratoriesLifeLiverMediatingMedicalMethodsMonitorMorbidity - disease rateMusNon-Insulin-Dependent Diabetes MellitusOutcome StudyPancreasPancreatic ductPatient-Focused OutcomesPatientsPeptide HydrolasesPhasePlasmaPlasma ProteinsPreclinical TestingProcessProductionPropertyProteinsPublishingQuality of lifeRecombinant ProteinsRecombinantsRegulationReplacement TherapyResearchSerine Proteinase InhibitorsSerpinsSignal PathwayStructure of beta Cell of isletT-LymphocyteTechnologyTestingTherapeutic EffectTissuesToxicologyTranslatingTransplantationWorkalpha 1-Antitrypsinbaseburden of illnessclinical candidateclinically relevantcytokinedesigndisorder controlearly childhoodeffective therapyefficacy studyelastase inhibitorexperienceglobal healthimmunogenicityimmunoregulationimprovedin vivoin vivo Modelinsulin dependent diabetes mellitus onsetisletislet allograftislet cell antibodymortalitymouse modelnovelpre-clinicalpreservationpreventresearch clinical testingresponseskillstreatment effect
项目摘要
The number of people with diabetes worldwide is predicted to increase from 415 million in 2015 to 642 million in 2040. The health care costs of treating the disease account for 12% of the global health expenditure and continue to be a huge economic burden (IDF World Atlas 2015). Type 1 diabetes mellitus (T1DM) constitutes 10-15% of the disease burden. It is an autoimmune disease, thought to be triggered by genetic or environmental factors in early childhood, which results in antibody- mediated destruction of insulin producing pancreatic β-cells causing life-threatening hyperglycemia. In contrast, type 2 diabetes mellitus (T2DM) develops later in life and results from insulin resistance in target tissues and inflammation coupled with an inadequate compensation by the β-cells. A major limitation in effectively treating both forms of the disease is preventing a decline in β- cell function and/or mass. Recently, the Kulkarni lab identified Serpin B1 (an intracellular SERine Proteinase Inhibitor) as a liver-derived protein factor that promotes a compensatory β-cell response by inhibiting elastase and inducing β-cell proliferation in multiple species by activating growth/survival factor signaling pathways. The structurally and functionally related human plasma protein alpha 1- antitrypsin (AAT, serpin A1) is in late stage clinical trials to delay the onset of T1DM after a majority of independent studies showed it could restore euglycemia in animal models of T1DM by preserving functional β-cells, enhancing islet allograft survival and modulating cellular immunity. Early stage clinical study results indicate that AAT reduces HbA1c levels and anti-islet cell antibody titers. Serpin B1 (sB1), like AAT, is an effective anti-inflammatory elastase inhibitor but unlike AAT, also induces β-cell proliferation, promotes insulin + cells in pancreatic ductal lining epithelia, inhibits NETosis (another pro-inflammatory process involved in diabetes) and regulates the expansion of Th17 cytokine producing cells in vitro. We therefore propose that sB1 may also work in vivo, either alone or in combination with AAT, to provide superior therapeutic effects in animal models of T1DM. We will test if sB1 -/+ AAT can more effectively prevent the onset of, or treat established, T1DM in the NOD mouse model by inducing proliferation of functional β-cells, enhancing production of insulin by ductal lining cells and protecting β-cells from the immune response. If successful, we will further develop this technology through preclinical and clinical testing with the intent to improve long-term outcome for patients with T1DM. The proposed research in phase I will focus on (Aim 1) producing highly purified active recombinant proteins and (Aim 2) providing proof-of-principle in animal models of T1DM. The outcome of these studies will guide the design of future efficacy studies in animals and humans.
全球糖尿病患者人数预计将从2015年的4.15亿增加到2040年的6.42亿。治疗疾病的医疗保健费用占全球卫生支出的12%,并继续成为巨大的经济负担(IDF World Atlas 2015)。1型糖尿病(T1 DM)占疾病负担的10-15%。它是一种自身免疫性疾病,被认为是由儿童早期的遗传或环境因素触发的,其导致抗体介导的胰岛素产生胰腺β细胞的破坏,从而引起危及生命的高血糖症。相比之下,2型糖尿病(T2 DM)在生命后期发展,由靶组织中的胰岛素抵抗和炎症以及β细胞补偿不足引起。 有效治疗这两种形式的疾病的主要限制是防止β细胞功能和/或质量下降。最近,Kulkarni实验室将Serpin B1(一种细胞内丝氨酸蛋白酶抑制剂)鉴定为一种肝源性蛋白因子,通过抑制弹性蛋白酶促进代偿性β细胞反应,并通过激活生长/存活因子信号通路诱导多种物种的β细胞增殖。结构和功能相关的人血浆蛋白α 1-抗胰蛋白酶(AAT,serpin A1)在延迟T1 DM发作的后期临床试验中,大多数独立研究表明,它可以通过保留功能性β细胞,增强胰岛移植物存活和调节细胞免疫来恢复T1 DM动物模型中的正常功能。早期临床研究结果表明,AAT降低HbA 1c水平和抗胰岛细胞抗体滴度。 Serpin B1(sB 1)与AAT一样,是一种有效的抗炎弹性蛋白酶抑制剂,但与AAT不同的是,它还诱导β-细胞增殖,促进胰腺导管衬里上皮中的胰岛素+细胞,抑制NETosis(糖尿病中涉及的另一种促炎过程),并在体外调节Th 17细胞因子产生细胞的扩增。因此,我们提出sB 1也可能在体内起作用,单独或与AAT联合,在T1 DM动物模型中提供上级治疗效果。我们将在NOD小鼠模型中检测sB 1-/+ AAT是否可以通过诱导功能性β细胞增殖、增强导管内衬细胞产生胰岛素和保护β细胞免受免疫应答影响,更有效地预防或治疗已建立的T1 DM。如果成功,我们将通过临床前和临床试验进一步开发这项技术,旨在改善T1 DM患者的长期结局。第一阶段拟议的研究将重点关注(目标1)生产高纯度活性重组蛋白和(目标2)在T1 DM动物模型中提供原理验证。这些研究的结果将指导未来动物和人类有效性研究的设计。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ROHIT N. KULKARNI其他文献
ROHIT N. KULKARNI的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ROHIT N. KULKARNI', 18)}}的其他基金
Interrogating the ubiquitin pathway to understand and treat cytokine-induced beta-cell death in type 1 diabetes
探究泛素通路以了解和治疗 1 型糖尿病中细胞因子诱导的 β 细胞死亡
- 批准号:
10278303 - 财政年份:2021
- 资助金额:
$ 21.84万 - 项目类别:
Interrogating the ubiquitin pathway to understand and treat cytokine-induced beta-cell death in type 1 diabetes
探究泛素通路以了解和治疗 1 型糖尿病中细胞因子诱导的 β 细胞死亡
- 批准号:
10477373 - 财政年份:2021
- 资助金额:
$ 21.84万 - 项目类别:
Enhanced pancreatic islet cell engraftment by treatment with serpin B1
丝氨酸蛋白酶抑制剂 B1 处理增强胰岛细胞植入
- 批准号:
10383270 - 财政年份:2021
- 资助金额:
$ 21.84万 - 项目类别:
Interplay between SerpinB1 and TLR2/TLR4 in beta cell regeneration
SerpinB1 和 TLR2/TLR4 在 β 细胞再生中的相互作用
- 批准号:
10094305 - 财政年份:2020
- 资助金额:
$ 21.84万 - 项目类别:
One-compound, one-islet: A high-throughput platform for small-molecule discovery
一种化合物,一种胰岛:用于小分子发现的高通量平台
- 批准号:
10450745 - 财政年份:2019
- 资助金额:
$ 21.84万 - 项目类别:
One-compound, one-islet: A high-throughput platform for small-molecule discovery
一种化合物,一种胰岛:用于小分子发现的高通量平台
- 批准号:
10356005 - 财政年份:2019
- 资助金额:
$ 21.84万 - 项目类别:
Interplay Between SERPINB1 and TLR2/TLR4 in Beta Cell Regeneration
SERPINB1 和 TLR2/TLR4 在 Beta 细胞再生中的相互作用
- 批准号:
10301008 - 财政年份:2018
- 资助金额:
$ 21.84万 - 项目类别:
Interplay Between SERPINB1 and TLR2/TLR4 in Beta Cell Regeneration
SERPINB1 和 TLR2/TLR4 在 Beta 细胞再生中的相互作用
- 批准号:
10378332 - 财政年份:2018
- 资助金额:
$ 21.84万 - 项目类别:
Interplay Between SERPINB1 and TLR2/TLR4 in Beta Cell Regeneration
SERPINB1 和 TLR2/TLR4 在 Beta 细胞再生中的相互作用
- 批准号:
10062405 - 财政年份:2018
- 资助金额:
$ 21.84万 - 项目类别:
Role of 12-lipoxygenase and 12-HETE signaling in beta-cell dysfunction
12-脂氧合酶和 12-HETE 信号在 β 细胞功能障碍中的作用
- 批准号:
10853540 - 财政年份:2015
- 资助金额:
$ 21.84万 - 项目类别:
相似海外基金
The earliest exploration of land by animals: from trace fossils to numerical analyses
动物对陆地的最早探索:从痕迹化石到数值分析
- 批准号:
EP/Z000920/1 - 财政年份:2025
- 资助金额:
$ 21.84万 - 项目类别:
Fellowship
Animals and geopolitics in South Asian borderlands
南亚边境地区的动物和地缘政治
- 批准号:
FT230100276 - 财政年份:2024
- 资助金额:
$ 21.84万 - 项目类别:
ARC Future Fellowships
The function of the RNA methylome in animals
RNA甲基化组在动物中的功能
- 批准号:
MR/X024261/1 - 财政年份:2024
- 资助金额:
$ 21.84万 - 项目类别:
Fellowship
Ecological and phylogenomic insights into infectious diseases in animals
对动物传染病的生态学和系统发育学见解
- 批准号:
DE240100388 - 财政年份:2024
- 资助金额:
$ 21.84万 - 项目类别:
Discovery Early Career Researcher Award
Zootropolis: Multi-species archaeological, ecological and historical approaches to animals in Medieval urban Scotland
Zootropolis:苏格兰中世纪城市动物的多物种考古、生态和历史方法
- 批准号:
2889694 - 财政年份:2023
- 资助金额:
$ 21.84万 - 项目类别:
Studentship
Using novel modelling approaches to investigate the evolution of symmetry in early animals.
使用新颖的建模方法来研究早期动物的对称性进化。
- 批准号:
2842926 - 财政年份:2023
- 资助金额:
$ 21.84万 - 项目类别:
Studentship
Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research
研究人类晚期胎儿肺组织和 3D 体外类器官在肺发育研究中替代和减少动物
- 批准号:
NC/X001644/1 - 财政年份:2023
- 资助金额:
$ 21.84万 - 项目类别:
Training Grant
RUI: Unilateral Lasing in Underwater Animals
RUI:水下动物的单侧激光攻击
- 批准号:
2337595 - 财政年份:2023
- 资助金额:
$ 21.84万 - 项目类别:
Continuing Grant
RUI:OSIB:The effects of high disease risk on uninfected animals
RUI:OSIB:高疾病风险对未感染动物的影响
- 批准号:
2232190 - 财政年份:2023
- 资助金额:
$ 21.84万 - 项目类别:
Continuing Grant
A method for identifying taxonomy of plants and animals in metagenomic samples
一种识别宏基因组样本中植物和动物分类的方法
- 批准号:
23K17514 - 财政年份:2023
- 资助金额:
$ 21.84万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)