Genetic programming of human islet metabolic and endoplasmic reticulum (ER) stress responses in diabetes
糖尿病患者胰岛代谢和内质网(ER)应激反应的基因编程
基本信息
- 批准号:10531894
- 负责人:
- 金额:$ 77.84万
- 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:2020-12-03 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAllelesApoptosisBeta CellBindingBiological AssayCRISPR/Cas technologyCell LineCell ProliferationCell SurvivalChromatinClustered Regularly Interspaced Short Palindromic RepeatsCompensationComplementComplexComputer AnalysisCustomDataDiabetes MellitusDiseaseEndoplasmic ReticulumEtiologyExposure toFailureFunctional disorderFundingGene ExpressionGenesGeneticGenetic ProgrammingGenetic RiskGenetic TranscriptionGenetic VariationGenomicsGenotypeGlucoseGuide RNAHealth systemHumanHuman GeneticsIndividualInflammatoryInsulinInsulin ResistanceIslets of LangerhansKnowledgeLinkLocationMeasuresMedicalMetabolicMetabolic stressMolecularNon-Insulin-Dependent Diabetes MellitusPalmitatesPathogenesisPathway interactionsPeripheralPhysiological ProcessesPredispositionProteinsPublic HealthQuantitative Trait LociRNA libraryRegulationRegulatory ElementReporterRepressionResearchResistanceRiskSingle Nucleotide PolymorphismStressTechnologyTestingThapsigarginTissuesTranscriptional RegulationTransposaseTunicamycinVariantbiological adaptation to stresscellular resiliencecytokinediabetes pathogenesisdiabetes riskdiabetogenicendoplasmendoplasmic reticulum stressepigenomicsgenetic manipulationgenetic variantgenome editinggenome wide association studygenome-widegenomic locusin vivoinnovationinsightisletloss of functionnew therapeutic targetnon-diabeticoverexpressionpreventresponsesingle-cell RNA sequencingstressortraittranscription factortranscriptome sequencing
项目摘要
PROJECT SUMMARY
Type 2 diabetes (T2D) results from failure of pancreatic islets to secrete sufficient insulin to compensate for
increased insulin resistance in peripheral tissues. Precise understanding of the molecular mechanisms
underlying genetic and environmental contributions to islet failure is essential to develop new, targeted
approaches to prevent and treat T2D. Endoplasmic reticulum (ER) and (gluco)lipotoxic stress responses are
central (patho)physiologic processes that contribute to islet dysfunction and failure. Our overall objective in this
proposal is to elucidate the genetic regulation of islet stress responses and to determine how genetic variants,
including SNPs associated with T2D and other metabolic traits (T2D SNPs), modulate these responses to
contribute to islet dysfunction and T2D pathogenesis. Based on previous studies and preliminary data, we
hypothesize that T2D SNPs alter human islet stress responses by changing islet regulatory element (RE)
use/function and expression of their target genes to contribute to islet dysfunction and T2D. In Aim 1, we will
test this hypothesis by characterizing islet ER and (gluco)lipotoxic stress responses at the level of gene
expression and identifying genetic variants altering human islet stress responses. For this, we will use bulk and
single-cell RNA-Seq as well as computational analyses to discover response expression quantitative trait loci
(reQTL). In Aim 2, we will take a complementary epigenomic approach to elucidate genetic effects on stress
response regulatory element (RE) use in human islets. From the same islets as in Aim 1, we will determine the
genome-wide location of REs at steady state and after exposure to stressors using the assay for transposase
accessible chromatin-sequencing (ATAC-seq). Using these data, we will computationally identify transcription
factors binding to these REs, identify genetic variants altering stress-responsive RE use by chromatin
accessibility quantitative trait locus (caQTL) analyses, and test allelic effects on stress-responsive RE activity
using massively parallel reporter assays (MPRA) in beta cell lines. Finally, we will experimentally manipulate
these islet stress-responsive genes in human EndoC-ßH3 beta cells using CRISPR/Cas9 (epi)genome editing
to determine their functions in beta cell proliferation, function, and survival (Aim 3). This study will provide
mechanistic insight into how human genetic variation modulates these T2D-relevant stress responses in
human islets. By delineating the genes and pathways that modulate islet (gluco)lipotoxic and ER stress
responses and experimentally validating their effects on islet/beta cell resilience, this study will reveal novel
therapeutic targets and guide strategies for subsequent studies manipulating these responses to prevent or
treat islet failure and T2D.
项目摘要
2型糖尿病(T2 D)是由于胰岛不能分泌足够的胰岛素以补偿胰岛素分泌不足而导致的。
外周组织胰岛素抵抗增加。对分子机制的精确理解
潜在的遗传和环境因素对胰岛功能衰竭的影响对于开发新的、有针对性的
预防和治疗T2 D的方法内质网(ER)和(葡萄糖)脂毒性应激反应是
导致胰岛功能障碍和衰竭的中枢(病理)生理过程。我们在这方面的总体目标
建议是阐明胰岛应激反应的遗传调节并确定遗传变异如何,
包括与T2 D和其他代谢性状相关的SNP(T2 D SNP),调节这些反应,
有助于胰岛功能障碍和T2 D发病机制。根据以前的研究和初步数据,我们
假设T2 D SNP通过改变胰岛调节元件(RE)改变人类胰岛应激反应
它们的靶基因的用途/功能和表达有助于胰岛功能障碍和T2 D。在目标1中,我们
通过在基因水平上表征胰岛ER和(葡萄糖)脂毒性应激反应来验证这一假设。
表达和鉴定改变人胰岛应激反应的遗传变体。为此,我们将使用批量和
单细胞RNA-Seq以及计算机分析,以发现响应表达数量性状基因座
(reQTL)。在目标2中,我们将采用互补的表观基因组方法来阐明遗传对压力的影响
反应调节元件(RE)在人类胰岛中的应用。从与目标1相同的胰岛,我们将确定
使用转座酶测定法在稳态和暴露于应激物后RE的全基因组定位
可访问染色质测序(ATAC-seq)。利用这些数据,我们将通过计算确定转录
与这些RE结合的因子,鉴定改变染色质应激反应性RE使用的遗传变体
可及性数量性状基因座(caQTL)分析,并测试等位基因对应激反应RE活性的影响
在β细胞系中使用大规模平行报告基因测定(MPRA)。最后,我们将实验性地操纵
使用CRISPR/Cas9(epi)基因组编辑,
以确定它们在β细胞增殖、功能和存活中的功能(目的3)。本研究将提供
对人类遗传变异如何调节这些T2 D相关应激反应的机械见解,
人类的小岛通过描述调节胰岛(葡萄糖)脂毒性和ER应激的基因和途径,
反应和实验验证其对胰岛/β细胞弹性的影响,这项研究将揭示新的
治疗目标和指导策略,用于随后的研究操纵这些反应,以防止或
治疗胰岛衰竭和T2 D。
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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Michael Lee Stitzel其他文献
Michael Lee Stitzel的其他文献
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{{ truncateString('Michael Lee Stitzel', 18)}}的其他基金
Genetic programming of human islet metabolic and endoplasmic reticulum (ER) stress responses in diabetes
糖尿病患者胰岛代谢和内质网(ER)应激反应的基因编程
- 批准号:
10311552 - 财政年份:2020
- 资助金额:
$ 77.84万 - 项目类别:
Regulation and Function of the Type 2 Diabetes-Associated C2CD4A/B Locus
2 型糖尿病相关 C2CD4A/B 基因座的调节和功能
- 批准号:
10304883 - 财政年份:2019
- 资助金额:
$ 77.84万 - 项目类别:
Regulation and Function of the Type 2 Diabetes-Associated C2CD4A/B Locus
2 型糖尿病相关 C2CD4A/B 基因座的调节和功能
- 批准号:
10531864 - 财政年份:2019
- 资助金额:
$ 77.84万 - 项目类别:
Investigation of noncoding variation in human pancreatic islets and their develop
人胰岛非编码变异的研究及其发展
- 批准号:
8827485 - 财政年份:2014
- 资助金额:
$ 77.84万 - 项目类别:
Investigation of noncoding variation in human pancreatic islets and their develop
人胰岛非编码变异的研究及其发展
- 批准号:
9143741 - 财政年份:2014
- 资助金额:
$ 77.84万 - 项目类别:
Investigation of noncoding variation in human pancreatic islets and their develop
人胰岛非编码变异的研究及其发展
- 批准号:
9037997 - 财政年份:2014
- 资助金额:
$ 77.84万 - 项目类别:
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