Cell Cycle Control Of Beta Cell Mass

β细胞团的细胞周期控制

• 批准号: 8299092
• 负责人: Anil Bhushan
• 金额: $ 34.93万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-05 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299092
• 关键词: Address; Adult; Age; Aging; Beta Cell; Binding; Breeding; CDKN2A gene; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Nucleus; Cell Proliferation; Cells; Complementary DNA; Complex; Data; Diabetes Mellitus; Dissociation; Epigenetic Process; Fostering; Funding; G1 Phase; G2 Phase; Genes; Genotype; Grant; Growth; Growth and Development function; Imaging Device; Immune Sera; Individual; Injury; Insulin; Insulin Resistance; Knock-in Mouse; Knockout Mice; Laboratories; Lead; Life; Light; Mediating; Metabolic; Methods; Mitosis; Modeling; Molecular; Monitor; Mus; Mutant Strains Mice; Natural regeneration; Paper; Pattern; Performance; Physiological; Play; Polycomb; Publishing; Reagent; Regulation; Repression; S Phase; System; Technology; Testing; Time; Transgenic Mice; Work; age related; base; cell growth; cyclin D2; design; diabetic patient; genome-wide analysis; high risk; in vivo; islet; medical complication; member; novel; novel therapeutic intervention; pancreas development; postnatal; public health relevance; sensor; spatiotemporal

DESCRIPTION (provided by applicant): Understanding the molecular mechanisms that regulate beta cell mass have important ramifications for fostering beta cell regeneration and the treatment of diabetes. Studies supported by this grant have established the importance of beta cell replication in regulating beta cell mass during growth, physiological expansion and regeneration. During the past funding cycle, we have shown that cyclin D2 plays a key role not only in establishing beta cell mass but also in adapting to insulin resistance. We established how metabolic changes lead to modulation of beta cell mass by mechanisms that regulate the cellular abundance of p27. Recently, we have shown that the age-dependent capacity of beta cells to replicate declines with age and is regulated by polycomb genes that control the levels of cell cycle regulator, p16Ink4a by epigenetic mechanisms. In the next five years we propose to design epigenetic strategies that can enhance beta cell replication in adults, test the requirements of beta cell replication in injury models of regeneration and develop new imaging tools to visualize beta cell replication during growth, development and regeneration. We propose to study: Aim 1, whether increased Ezh2 levels in beta cells in vivo can inhibit p16Ink4a, promote beta cell replication and enhance beta cell regeneration in adult mice; in Aim 2, study the mechanism by which Brg1 regulates beta cell replication in vivo by generating and analyzing mice that lack Brg1 in beta cells and carry out genome-wide analysis of Brg1 targets on cell cycle regulators in beta cells; in Aim 3, assess whether introduction of cyclin D2 into beta cells of cyclin D2 null mice is sufficient for beta cell growth and regeneration; in Aim 4, propose to monitor the spatiotemporal patterns of cell-cycle dynamics during pancreas development, growth in postnatal period and regeneration using a novel transgenic mouse system with fluorescent sensors. These studies will be carried out using null mouse mutants, beta cell-specific inducible transgenic mice, and cultured islet, using methods that are fully implemented in the laboratory. A major overall strength of this proposal is that we have already generated or obtained all the mice described here as well as assessed their breeding performance, and have carried out intercrosses to verify our ability to generate desired genotypes. PUBLIC HEALTH RELEVANCE: As diabetic patients require life-long insulin therapy and have a high risk of medical complications, preventative or curative therapies are urgently needed. Diabetes results from an inadequate mass of functional beta cells and there is increasing evidence to suggests that replication of beta cell is the dominant means by which beta cells adapt to changing metabolic demands and during regeneration. This proposal contends that understanding the mechanisms of beta cell regeneration could be useful for regenerating beta cells and such an approach that exploits the mechanisms involved in the expansion of beta cell mass due to physiologic demands will be critical in developing novel therapeutic approaches that involve beta-cell regeneration in diabetic patients.

描述（由申请人提供）：了解调节 β 细胞质量的分子机制对于促进 β 细胞再生和治疗糖尿病具有重要影响。该资助支持的研究已经确定了β细胞复制在生长、生理扩张和再生过程中调节β细胞质量的重要性。 在过去的资助周期中，我们已经证明细胞周期蛋白 D2 不仅在建立 β 细胞团方面发挥着关键作用，而且在适应胰岛素抵抗方面也发挥着关键作用。我们确定了代谢变化如何通过调节 p27 细胞丰度的机制来调节 β 细胞质量。最近，我们发现β细胞的年龄依赖性复制能力随着年龄的增长而下降，并受到多梳基因的调节，多梳基因通过表观遗传机制控制细胞周期调节因子p16Ink4a的水平。在接下来的五年中，我们建议设计表观遗传策略，以增强成人β细胞复制，测试再生损伤模型中β细胞复制的要求，并开发新的成像工具来可视化生长、发育和再生过程中的β细胞复制。我们拟研究：目标1，成年小鼠体内β细胞中Ezh2水平升高是否可以抑制p16Ink4a，促进β细胞复制并增强β细胞再生； 目标2，通过生成和分析β细胞中缺乏Brg1的小鼠，研究Brg1在体内调节β细胞复制的机制，并对β细胞中细胞周期调节因子的Brg1靶点进行全基因组分析；在目标 3 中，评估将细胞周期蛋白 D2 引入细胞周期蛋白 D2 缺失小鼠的 β 细胞中是否足以促进 β 细胞生长和再生；在目标 4 中，建议使用带有荧光传感器的新型转基因小鼠系统监测胰腺发育、产后生长和再生过程中细胞周期动态的时空模式。 这些研究将使用无效小鼠突变体、β细胞特异性诱导转基因小鼠和培养胰岛，并使用完全在实验室中实施的方法进行。该提案的主要整体优势在于，我们已经生成或获得了此处描述的所有小鼠，并评估了它们的繁殖性能，并进行了杂交以验证我们生成所需基因型的能力。 公共卫生相关性：由于糖尿病患者需要终生胰岛素治疗并且出现医疗并发症的风险很高，因此迫切需要预防性或治疗性治疗。糖尿病是由功能性β细胞数量不足引起的，越来越多的证据表明β细胞的复制是β细胞适应不断变化的代谢需求和再生过程的主要手段。该提案认为，了解 β 细胞再生的机制可能有助于再生 β 细胞，而这种利用因生理需求而导致 β 细胞质量扩张的机制的方法对于开发涉及糖尿病患者 β 细胞再生的新治疗方法至关重要。