Cloning of a type 2 diabetes modifier in obese mice

在肥胖小鼠中克隆 2 型糖尿病调节剂

• 批准号: 7524305
• 负责人: RUDOLPH L LEIBEL
• 金额: $ 40.08万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7524305
• 关键词: Ablation; Accounting; Adenoviruses; Affect; Age; Alleles; American; Animals; Beta Cell; Biological Assay; Biological Process; Blindness; Brain; Candidate Disease Gene; Cardiovascular Diseases; Cell Count; Cell Proliferation; Cell physiology; Cells; Cellular biology; Characteristics; Chromosome Mapping; Cloning; Congenic Mice; Critical Pathways; Developed Countries; Development; Diabetes Mellitus; Disruption; Employee Strikes; End stage renal failure; Etiology; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Genetic Crosses; Genetic Predisposition to Disease; Glucose; Health Care Costs; Homeostasis; Human; Human Genome; Hyperglycemia; Immunohistochemistry; Impairment; Inbred Strain; Incidence; Individual; Induced Mutation; Insulin; Insulin Resistance; Islet Cell; Islets of Langerhans; Left; Link; Liver; Location; Maps; Mediating; Medical; Metabolic; Methods; Minority; Molecular; Molecular Genetics; Mouse Strains; Mus; Neonatal; Non-Insulin-Dependent Diabetes Mellitus; Nonsense Mutation; Numbers; Obese Mice; Obesity; Organ; Orthologous Gene; Pancreas; Phenotype; Physiology; Play; Population; Prediabetes syndrome; Predisposition; Prevalence; Process; Production; Property; Protein Biosynthesis; Proteins; Public Health; Rate; Research Design; Resistance; Role; Signal Transduction; Small Interfering RNA; Stress; Structure-Activity Relationship; Techniques; Testing; Time; Tissues; Transcript; Transgenic Organisms; United States; Zebrafish; aged; base; congenic; cost; day; design; gain of function; genetic analysis; in vivo; islet; lipid metabolism; lipolysis-stimulated receptor; loss of function; mortality; mouse genome; novel; ranpirnase; research study

DESCRIPTION (provided by applicant): Over 7% (21M) of the U.S. population has diabetes (over 90% of which is type 2 = T2D). Another 54M have "prediabetes" (all T2D). The human tragedy aside, direct medical costs associated with diabetes in the United States currently exceed $132 billion a year and consume ~10% of health care costs in industrialized nations. Diabetes is the leading cause of both end stage renal disease and blindness (in people aged 20-74 years), and its association with cardiovascular disease increases mortality rates two-fold. The worldwide prevalence of T2D is projected to more than double over the next 20 years. Although intensive genetic analyses of human populations have confirmed contributory roles for some specific genes, these cannot account - even in the aggregate - for powerful genetic predisposition T2D. Obesity is clearly related to the occurrence of diabetes. Physiologically, this is apparently due to the stress that obesity-related insulin resistance places on the insulin- producing cells of the pancreas. But the molecular basis for this striking association is not known. It is possible that part of this differential susceptibility derives from genetically mediated differences in the starting numbers of insulin producing beta cells among individuals. If so, it is very important to identify the relevant genes. Mouse strains differ widely in susceptibility to diabetes when made obese. We exploited this characteristic to map diabetes-susceptibility regions of the mouse genome in genetics crosses between a diabetes-susceptible and a resistant strain. We used molecular genetic methods to find a novel gene, lisch-like (Ll) that appears to account for some aspects of this strain-related difference in mice. The gene affects the early development and replication of beta cells, leaving animals with the susceptible version of the gene with a reduced beta cell mass that then predisposes them to diabetes. The proposed studies are intended to confirm the role of this gene in the etiology of T2D and to reveal how this novel molecule produces these effects. The Hypothesis underlying the proposed studies is that LL regulates generation and survival of islet beta cells. In Aim 1 we will examine the systemic and cellular physiology of mice with induced mutations causing under or over-activity of the Ll gene. These studies are designed to confirm the gene's role in diabetes and to understand the molecular physiology of its activity. In Aim 2 Assays of protein biosynthesis, processing, and sub-cellular localization, signaling properties and structure/function relationships will be employed in gain- and loss-of-function experiments of LL. The human version of the Ll gene is 90% identical to that in the mouse, and is located in a region of the human genome that has been repeatedly linked to T2D in genetic studies. Ll could play a role in that linkage. Elucidation of the mechanisms by which LL loss-of-function produces diabetes-susceptibility may reveal novel pathways critical to cell development and survival in the context of insulin resistance and gluco-/lipotoxicity imposed by obesity. PUBLIC HEALTH RELEVANCE: Nearly twenty one million people in the United States (over 7% of the population), and over 246 million people worldwide are afflicted with type 2 diabetes (T2D); about 54 million Americans have pre-diabetes. If the incidence of T2D continues to increase at the present rate, one in three Americans, and 1 in 2 minorities, born in 2000 will develop diabetes in their lifetime. This project will analyze the molecular function of a newly discovered gene that may account for some aspects of diabetes susceptibility in humans.

描述(由申请人提供)：超过7%(2100万)的美国人口患有糖尿病(其中90%以上为2型=T2D)。另有5400万人患有“糖尿病前期”(均为T2D)。撇开人类悲剧不谈，美国与糖尿病相关的直接医疗费用目前每年超过1320亿美元，消耗了工业化国家约10%的医疗费用。糖尿病是终末期肾病和失明的主要原因(在20-74岁的人群中)，它与心血管疾病的关联使死亡率增加了两倍。预计T2D在全球的流行率在未来20年将增加一倍以上。尽管对人类群体的密集遗传分析已经证实了某些特定基因的贡献作用，但这些不能解释--即使是总体上--强大的遗传易感性T2D。肥胖显然与糖尿病的发生有关。从生理上讲，这显然是由于肥胖相关的胰岛素抵抗对胰腺的胰岛素产生细胞施加了压力。但这种惊人联系的分子基础尚不清楚。这种不同的易感性可能部分来自于个体之间产生胰岛素的β细胞起始数量的遗传差异。如果是这样的话，识别相关基因是非常重要的。当小鼠变胖时，它们对糖尿病的易感性差异很大。我们利用这一特征，在糖尿病易感品系和耐药品系之间的遗传学杂交中绘制了小鼠基因组的糖尿病易感区域。我们使用分子遗传学方法找到了一个新的基因，Lisch-like(LL)，它似乎解释了小鼠这种品系相关差异的某些方面。该基因影响贝塔细胞的早期发育和复制，使动物携带该基因的易感版本的贝塔细胞质量减少，从而使它们容易患上糖尿病。拟议的研究旨在证实该基因在T2D的病因学中的作用，并揭示这种新的分子如何产生这些效应。支持这项研究的假设是，LL调节胰岛β细胞的生成和存活。在目标1中，我们将检查诱导突变导致LL基因活性低下或过度的小鼠的系统和细胞生理学。这些研究旨在确认该基因在糖尿病中的作用，并了解其活动的分子生理学。在目标2中，蛋白质的生物合成、加工和亚细胞定位、信号特性和结构/功能关系将被用于LL的获得和功能丧失的实验。人类版本的LL基因与小鼠的版本90%相同，位于人类基因组中的一个区域，该区域在遗传学研究中已多次与T2D相关联。LL可以在这种联系中发挥作用。阐明L1功能丧失导致糖尿病易感性的机制可能揭示在肥胖造成的胰岛素抵抗和糖脂毒性背景下对细胞发育和生存至关重要的新途径。公共卫生相关性：美国近2100万人(占总人口的7%以上)和全球超过2.46亿人患有2型糖尿病(T2D)；约5400万美国人患有糖尿病前期。如果T2D的发病率继续以目前的速度增加，2000年出生的美国人中有1/3和少数民族中有1/2将在一生中患上糖尿病。该项目将分析一种新发现的基因的分子功能，该基因可能解释人类糖尿病易感性的某些方面。