AGE DEPENDENT REGULATION OF HEMOSTASIS

年龄依赖性止血调节

• 批准号: 6390655
• 负责人: KOTOKU KURACHI
• 金额: $ 34.95万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390655
• 关键词: aging; artificial chromosomes; coagulation factor IX; disease /disorder model; gene expression; genetic models; genetic regulatory element; genetically modified animals; hemostasis; homeostasis; human puberty; laboratory mouse; model design /development; thrombosis

DESCRIPTION: (Adapted from investigator's abstract) Blood coagulation activity in the normal human population elevates with advancing age. When combined with age-dependent disorders like atherosclerosis, this increase in the coagulation potential may play a role in the increased frequency of cardiovascular and thrombotic disorders in the elderly. Presently, little is known about the molecular mechanisms responsible for this phenomenon and homeostasis of the coagulation system in general. The long-term goal of this proposal is to determine the molecular mechanisms underlying age-dependent regulation and homeostasis of the blood coagulation system. The factor IX gene will serve as an initial model gene for intensive studies. Recently the applicant has identified two major activities associated with specific regions of the factor IX gene that are essential for age-dependent regulation of expression. This proposal has five specific aims. Specific Aim 1 is to establish the mechanisms of action of two cis-acting elements, AE5' (a PEA3 binding element) and AE3' (a sequence containing extensive dinucleotide repeats) in age-dependent regulation of the human factor IX gene. Specific Aim 2 is to delineate the switch mechanisms in expression of transcriptional factors over the puberty period. Specific Aim 3 is to identify potential additional gene structures with modifying activities on age-dependent regulation of the gene. Specific Aim 4 is to determine the physiological significance of advancing age-dependent elevation in factor IX gene expression by constructing a mouse model lacking such elevation in the endogenous mouse factor IX gene. Specific Aim 5 is to determine the biological significance of elevated or lowered plasma factor IX levels in relation to age. The molecular mechanisms established for the factor IX gene will facilitate subsequent studies on other key coagulation factors and regulators, laying the foundation for comprehensive understanding of the overall age-dependent regulation (homeostasis) of the coagulation system. Such knowledge may help develop novel and/or improved treatments for hemorrhagic disorders as well as thrombotic and cardiovascular diseases in the elderly.

描述：（改编自研究者的摘要）凝血活性 在正常人群中，随着年龄的增长而升高。当与 年龄依赖性疾病，如动脉粥样硬化，凝血功能增加 电位可能在心血管和心血管疾病频率增加中发挥作用 老年人的血栓性疾病。目前，人们对此知之甚少 造成这种现象和稳态的分子机制 一般凝血系统。该提案的长期目标是 确定年龄依赖性调节的分子机制和 凝血系统的稳态。 IX因子基因将充当 用于深入研究的初始模型基因。近期申请人有 确定了与该因素的特定区域相关的两项主要活动 IX 基因对于年龄依赖性表达调节至关重要。这 提案有五个具体目标。具体目标1是建立机制 两个顺式作用元件 AE5'（PEA3 结合元件）和 AE3'（PEA3 结合元件）的作用 包含大量二核苷酸重复的序列）在年龄依赖性调节中 人类IX因子基因。具体目标 2 是描绘开关 青春期转录因子表达的机制。 具体目标 3 是确定潜在的其他基因结构 改变基因年龄依赖性调节的活性。具体目标 4 是 确定随年龄增长的生理意义 通过构建缺乏因子IX的小鼠模型来提高因子IX基因的表达 内源性小鼠因子 IX 基因的这种升高。具体目标 5 是 确定血浆因子 IX 升高或降低的生物学意义 水平与年龄有关。该因子的分子机制已建立 IX基因将有助于后续其他关键凝血因子的研究 为监管者全面了解监管奠定基础 凝血系统的整体年龄依赖性调节（稳态）。这样的 知识可能有助于开发新的和/或改进的出血疗法 老年人的疾病以及血栓和心血管疾病。