The Diversity Outbred Diabetes Project

多样性远交糖尿病项目

• 批准号: 10376191
• 负责人: Alan D Attie
• 金额: $ 57.15万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376191
• 关键词: ATAC-seq; Affect; Animal Model; B-Cell Development; Beta Cell; Candidate Disease Gene; Cell physiology; Cellular biology; Collaborations; Communities; Cyclic AMP-Dependent Protein Kinases; Data; Data Set; Development; Diabetes Mellitus; Diet; Embryo; Epidemic; Gene Deletion; Generations; Genes; Genetic; Genetic Screening; Genetic Transcription; Genetic Variation; Genetic study; Glucagon; Human; Human Genetics; Inbred Strains Mice; Insulin; Insulin Resistance; Islets of Langerhans; Knock-out; Knockout Mice; Laboratories; Lead; Light; Link; Meiotic Recombination; Molecular; Mouse Strains; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Obesity Epidemic; Pathway interactions; Phenotype; Physiological; Play; Population; Population Genetics; Predisposition; Production; Quantitative Trait Loci; Research; Research Design; Resolution; Risk; Role; Signal Transduction; Single Nucleotide Polymorphism; Stimulus; Structure of beta Cell of islet; Testing; The Jackson Laboratory; Time; Variant; Vesicle; Viral; Work; bioinformatics pipeline; cell type; detection of nutrient; diabetes risk; gene discovery; gene function; genetic resource; genome wide association study; genomic locus; human embryonic stem cell; insight; insulin regulation; insulin secretion; islet; molecular phenotype; mouse genetics; novel; novel therapeutic intervention; patient stratification; response; trafficking; transcription factor; transcriptomics; web site

PROJECT SUMMARY/ABSTRACT Type 2 diabetes (T2D) is the result of an increased demand for insulin along with an inability of pancreatic β- cells to meet this demand by secreting sufficient amounts of insulin. The majority of gene loci identified by human genetic studies of T2D affect β-cell development, mass, and/or function. Yet, there is a great deal that is unknown about how β-cells secrete insulin in response to nutrient stimuli. We carried out a genetic screen of insulin secretion in 233,447 pancreatic islets ex vivo that were isolated from 483 Diversity Outbred (DO) mice. The DO mice were derived from 8 inbred mouse strains representing ~80% of the genetic diversity of all mouse strains. They have as much genetic diversity as the entire human population; ~40 million single nucleotide polymorphisms. The DO mice have been maintained for >30 generations, accumulating enough meiotic recombinations to enable high-resolution mapping of pathophysiological phenotypes. Our genetic screen identified 30 gene loci that affect insulin secretion or content of insulin or glucagon. Using our pipeline for gene identification, we chose two genes for further study, Hunk and Zfp148. We derived a whole-body knockout of Hunk and a β-cell-specific knockout of Zfp148. Islets from both of these knockout mice secreted more insulin in response to nutrient stimulation than control mice. Hunk is a protein kinase, thus we will identify the substrates of Hunk to discover how it regulates insulin secretion. Zfp148 is a transcription factor. Thus, we will identify the direct transcriptional targets of Zfp148. We will apply our bioinformatic pipeline to identify additional genes from the 30 gene loci identified in our screen and provide them to the research community. Functional studies will be performed in genetically edited mice, genetically edited human ES-derived β-cells, and human islets. These studies will discover novel genes and pathways involved in β-cell function and T2D susceptibility.

项目总结/摘要 2型糖尿病（T2 D）是对胰岛素的需求增加的结果，沿着胰腺β-葡萄糖缺乏。 细胞通过分泌足够量的胰岛素来满足这种需求。人类鉴定的大多数基因位点 T2 D的遗传学研究影响β细胞发育、质量和/或功能。然而，还有很多事情是未知的， 关于β细胞如何分泌胰岛素以应对营养刺激。我们对胰岛素进行了基因筛查 在离体的233，447个胰岛中，从483只Diversity Outbred（DO）小鼠中分离分泌。的DO 小鼠来源于8个近交系小鼠品系，代表所有小鼠品系遗传多样性的~80%。 它们的遗传多样性与整个人类人口一样多;约4000万个单核苷酸 多态性DO小鼠已经维持了>30代，积累了足够的减数分裂 重组以实现病理生理表型的高分辨率作图。我们的基因筛选 确定了30个影响胰岛素分泌或胰岛素或胰高血糖素含量的基因位点。用我们的管道 为了进一步鉴定，我们选择了两个基因，Hunk和Zfp 148。我们推导出了一种全身性的 Hunk和Zfp 148的β细胞特异性敲除。这两种基因敲除小鼠的胰岛分泌更多的胰岛素， 对营养刺激的反应比对照组小鼠。Hunk是一种蛋白激酶，因此我们将识别底物 来发现它是如何调节胰岛素分泌的Zfp 148是一种转录因子。因此，我们将确定 Zfp 148的直接转录靶点。我们将应用我们的生物信息学管道来识别来自 我们筛选出的30个基因位点，并将其提供给研究界。功能研究将是 在基因编辑的小鼠、基因编辑的人ES衍生的β细胞和人胰岛中进行。这些 研究将发现参与β细胞功能和T2 D易感性的新基因和途径。

项目成果

How mice are indispensable for understanding obesity and diabetes genetics.

• DOI: 10.1097/med.0000000000000321
• 发表时间: 2017-04
• 期刊: Current opinion in endocrinology, diabetes, and obesity
• 作者: Attie AD;Churchill GA;Nadeau JH
• 通讯作者: Nadeau JH

Sorting through the extensive and confusing roles of sortilin in metabolic disease.

• DOI: 10.1016/j.jlr.2022.100243
• 发表时间: 2022-08
• 期刊: JOURNAL OF LIPID RESEARCH
• 影响因子: 6.5
• 作者: Mitok, Kelly A.;Keller, Mark P.;Attie, Alan D.
• 通讯作者: Attie, Alan D.

From methylene bridged diindole to carbonyl linked benzimidazoleindole: Development of potent and metabolically stable PCSK9 modulators.

• DOI: 10.1016/j.ejmech.2020.112678
• 发表时间: 2020-11-15
• 期刊: European journal of medicinal chemistry
• 影响因子: 6.7
• 作者: Xie H;Yang K;Winston-McPherson GN;Stapleton DS;Keller MP;Attie AD;Smith KA;Tang W
• 通讯作者: Tang W

Coding variants identified in patients with diabetes alter PICK1 BAR domain function in insulin granule biogenesis.

• DOI: 10.1172/jci144904
• 发表时间: 2022-03-01
• 期刊: The Journal of clinical investigation
• 作者: Andersen RC;Schmidt JH;Rombach J;Lycas MD;Christensen NR;Lund VK;Stapleton DS;Pedersen SS;Olsen MA;Stoklund M;Noes-Holt G;Nielsen TT;Keller MP;Jansen AM;Herlo R;Pietropaolo M;Simonsen JB;Kjærulff O;Holst B;Attie AD;Gether U;Madsen KL
• 通讯作者: Madsen KL

Reversal of hypertriglyceridemia in diabetic BTBR ob/ob mice does not prevent nephropathy.

• DOI: 10.1038/s41374-021-00592-8
• 发表时间: 2021-07
• 期刊: LABORATORY INVESTIGATION
• 影响因子: 5
• 作者: Attie, Alan D;Schueler, Kathryn M;Keller, Mark P;Mitok, Kelly A;Simonett, Shane P;Hudkins, Kelly L;Mehrotra, Kunaal;Graham, Mark J;Lee, Richard G;Alpers, Charles E
• 通讯作者: Alpers, Charles E