Epigenetic Rejuvenation of Human Beta-Cells

人类β细胞的表观遗传复兴

• 批准号: 8811498
• 负责人: Benjamin Glaser
• 金额: $ 355.35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811498
• 关键词: 11p; Activities of Daily Living; Adolescent; Adult; Age; Aging; Aging-Related Process; Beckwith-Wiedemann Syndrome; Beta Cell; Blood Glucose; Budgets; C-Peptide; Cell Proliferation; Cell division; Cell physiology; Cells; Characteristics; Clinical; Developed Countries; Developing Countries; Diabetes Mellitus; Diabetic mouse; Disease; Distal; Emerging Technologies; Endocrine; Epidemic; Epigenetic Process; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genome; Genomics; Glucose; Goals; Health system; Healthcare; Hereditary Disease; Human; Human Genetics; Hyperinsulinism; Hyperplasia; Immune; In Vitro; Insulin; Intervention; Kidney; Knowledge; Laboratories; Maps; Mediating; Methods; Methylation; Modification; Molecular Abnormality; Molecular Biology; Molecular Genetics; Morbidity - disease rate; Multiple Endocrine Neoplasia Type 1; Mus; Mutation; Neoplasms; Pathway interactions; Patients; Phase; Population; Prevalence; Property; Protocols documentation; Rejuvenation; Research; Simulate; Structure of beta Cell of islet; Syndrome; Technology; Testing; Therapeutic; Translating; Transplantation; Viral; age related; aged; base; capsule; clinically relevant; epigenome; experience; expression vector; gene function; genetic manipulation; glucose tolerance; graft function; human disease; imprint; improved; improved functioning; in vivo; infancy; islet; mortality; neoplastic; normal aging; novel; public health relevance; research study; small hairpin RNA; success; therapeutic target; treatment strategy; type I and type II diabetes

DESCRIPTION (provided by applicant): The prevalence of Diabetes Mellitus has reached epidemic proportions world-wide and is predicted to increase rapidly in the years to come, putting a tremendous strain on health care budgets in both developed and developing countries. There are two major forms of diabetes and both are associated with decreased beta-cell mass. No treatments have been devised that increase beta-cell mass in vivo in humans, and transplantation of beta-cells is extremely limited due to lack of appropriate donors. For these reasons, increasing functional beta-cell mass in vitro, or in vivo prior to or after transplantatio, has become a "Holy Grail" of diabetes research. Our previous studies clearly show that adult human beta-cells can be induced to replicate, and - importantly - that cells can maintain normal glucose responsiveness after cell division. However, the replication rate achieved was still low, likely due in part to the known age-related decline in the ability of the beta-cell to replicate. W propose to build on our previous findings and to develop more efficacious methods to increase functional beta-cell mass by inducing replication of adult beta-cells, and by restoring juvenile functional properties to aged beta-cells. We will focus on mechanisms derived from studies of non- neoplastic human disease as well as age-related phenotypic changes in human beta-cells. In Aim 1, we will target the genes altered in patients with marked beta-cell hyperplasia, such as those suffering from Focal Hyperinsulinism of Infancy, Beckwith-Wiedemann Syndrome or Multiple Endocrine Neoplasia. Expression of these genes will be altered in human beta-cells via shRNA-mediated gene suppression and locus-specific epigenetic targeting. Success will be assessed in transplanted human islets by determination of beta-cell replication rate and retention of function. In Aim 2, we will determine the mechanisms of age-related decline in beta-cell function and replicative capacity, by mapping the changes in the beta-cell epigenome that occur with age. Selected genes will then be targeted as in Aim 1 to improve human beta-cell function, as assessed by glucose responsiveness. To accomplish these aims, we will use cutting-edge and emerging technologies that are already established or are being developed in our laboratories. The research team combines clinical experience with expertise in molecular biology and extensive experience in genomic modification aimed at enhancing beta-cell replication. By basing interventions on changes found in human disease and normal aging, this approach will increase the chances that discoveries made can be translated more rapidly into clinically relevant protocols.

描述（由申请人提供）：糖尿病的患病率已在世界范围内达到流行病的程度，预计在未来几年将迅速增加，给发达国家和发展中国家的医疗保健预算带来巨大压力。糖尿病有两种主要形式，两者都与 β 细胞质量减少有关。目前还没有设计出增加人体体内β细胞质量的治疗方法，并且由于缺乏合适的供体，β细胞的移植极其有限。由于这些原因，在体外或移植前后体内增加功能性β细胞量已成为糖尿病研究的“圣杯”。我们之前的研究清楚地表明，成人β细胞可以被诱导复制，而且重要的是，细胞在细胞分裂后可以维持正常的葡萄糖反应性。然而，所达到的复制率仍然很低，部分原因可能是由于已知的与年龄相关的β细胞复制能力下降。我们建议以我们之前的发现为基础，开发更有效的方法，通过诱导成体 β 细胞的复制和恢复老化 β 细胞的幼年功能特性来增加功能性 β 细胞质量。我们将重点关注源自人类非肿瘤疾病研究以及人类β细胞与年龄相关的表型变化的机制。在目标 1 中，我们将针对患有明显 β 细胞增生的患者（例如患有婴儿期局灶性高胰岛素血症、贝克威斯-维德曼综合征或多发性内分泌肿瘤的患者）中改变的基因。这些基因的表达将通过 shRNA 介导的基因抑制和位点特异性表观遗传靶向在人类 β 细胞中发生改变。将通过测定β细胞复制率和功能保留来评估移植的人类胰岛的成功。在目标 2 中，我们将通过绘制 β 细胞表观基因组随年龄变化而发生的变化，确定与年龄相关的 β 细胞功能和复制能力下降的机制。然后将按照目标 1 中的方式针对选定的基因，以改善人类 β 细胞功能（通过葡萄糖反应性进行评估）。为了实现这些目标，我们将使用实验室已经建立或正在开发的尖端和新兴技术。研究团队将临床经验与分子生物学专业知识以及旨在增强 β 细胞复制的基因组修饰方面的丰富经验相结合。通过基于人类疾病和正常衰老中发现的变化进行干预，这种方法将增加将所取得的发现更快转化为临床相关方案的机会。

项目成果

Epigenetic Analysis of Endocrine Cell Subtypes from Human Pancreatic Islets.

人类胰岛内分泌细胞亚型的表观遗传学分析。

• DOI: 10.1007/978-1-4939-6518-2_8
• 发表时间: 2017
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Zhang,Jia;Kaestner,KlausH
• 通讯作者: Kaestner,KlausH

Paternal Exercise Improves the Metabolic Health of Offspring via Epigenetic Modulation of the Germline.

• DOI: 10.3390/ijms23010001
• 发表时间: 2021-12-21
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Costa-Júnior JM;Ferreira SM;Kurauti MA;Bernstein DL;Ruano EG;Kameswaran V;Schug J;Freitas-Dias R;Zoppi CC;Boschero AC;Oliveira CAM;Santos GJ;Carneiro EM;Kaestner KH
• 通讯作者: Kaestner KH

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets.

维珍β细胞在胰岛中的新生态裂市场中持续存在。

• DOI: 10.1016/j.cmet.2017.03.017
• 发表时间: 2017-04-04
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: van der Meulen T;Mawla AM;DiGruccio MR;Adams MW;Nies V;Dólleman S;Liu S;Ackermann AM;Cáceres E;Hunter AE;Kaestner KH;Donaldson CJ;Huising MO
• 通讯作者: Huising MO

Glycemic control releases regenerative potential of pancreatic beta cells blocked by severe hyperglycemia.

血糖控制释放了被严重高血糖阻塞的胰腺β细胞的再生潜力。

• DOI: 10.1016/j.celrep.2022.111719
• 发表时间: 2022-11-29
• 期刊: Cell reports
• 影响因子: 8.8