AGE DEPENDENT REGULATION OF HEMOSTASIS

描述：(改编自研究人员摘要)凝血活性 在正常人群中随着年龄的增长而增加。当与 像动脉粥样硬化这样的年龄依赖性疾病，这种凝血功能的增加 潜伏期可能在心血管疾病和高血压的发生频率增加中起作用。 老年人的血栓性疾病。目前，人们对此知之甚少 导致这一现象的分子机制和细胞的动态平衡 一般的凝血系统。这项提议的长期目标是 确定年龄依赖性调控的分子机制和 凝血系统的动态平衡。因子IX基因将作为 一个用于密集研究的初始模型基因。最近，申请人已经 确定了与该要素的特定区域相关的两项主要活动 IX基因，对于年龄相关的表达调控是必不可少的。这 该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’(a 包含广泛二核苷酸重复的序列)在年龄相关的调节中 人类凝血因子IX基因。具体目标2是描述交换机 转录因子在青春期表达的机制。 具体目标3是识别潜在的附加基因结构 该基因的年龄依赖性调节的修饰活性。具体目标4是 确定年龄相关性增龄的生理学意义 通过构建缺乏的小鼠模型上调因子IX基因的表达 内源性小鼠第IX因子基因的这种升高。具体目标5是 测定血浆第IX因子升高或降低的生物学意义 与年龄相关的水平。为该因子建立的分子机制 IX基因将为后续研究其他关键凝血因子和 监管机构，为全面了解 凝血系统的整体年龄调节(动态平衡)。是这样的 知识可能有助于开发新的和/或改进的出血治疗方法 老年人的精神障碍以及血栓和心血管疾病。

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.