3'UTR Shortening In Pulmonary Vascular Disease

项目摘要 阿尔茨海默氏病（AD）是一种严重的大脑神经退行性疾病，在美国影响3500万人。 5.5在美国AD是最常见的痴呆形式，占病例的56%。 诊断后几年。有限的治疗可用于AD，并且它们不能延迟或停止AD的进展。 因此，迫切需要新的治疗方法。AD的特征是脑内 由淀粉样蛋白β（Aβ）组成的斑块，其被认为是早期致病事件。大多数AD病例 散发，65岁以后发展。最近的研究表明，Aβ的整体损伤 清除，而不是Aβ过度生产是关键的AD。AD中最常见的观察结果之一， 在高达98%的AD患者中存在脑淀粉样血管病（CAA）。最近的一项研究 表明脑中的血管平滑肌细胞（VSMCs）能够介导局部清除 Aβ。CAA也是脑血管疾病（CVD）颅内出血的主要触发因素。这 是重要的，因为有大量的文献证明CVD和AD之间的联系， 与痴呆症的相关性尽管血管系统在AD中的重要性，但Aβ清除率与AD的发病率之间的联系仍然存在。 通过血管平滑肌细胞和增加心血管疾病导致痴呆症还没有完全理解。NUDT 21，也称为 切割因子25（CFIm 25）是一种RNA结合蛋白，当耗尽时，其导致替代的 多聚腺苷酸化（阿帕）和整体3 'UTR缩短。我们对NUDT 21的研究表明， NUDT 21存在于AD患者的大脑中，并导致蛋白质转运和代谢的改变。 血管平滑肌细胞（VSMC）的处理途径。我们的总体假设是， 血管平滑肌NUDT 21破坏Aβ清除并使脑易患CVD。这将受到考验 具体目的如下：1-评估NUDT 21缺失和3 'UTR景观在AD中的作用; 2-确定 3-评估NUDT 21耗竭是否加剧CAA 脑血管病（CVD）。这些实验的成功完成有望揭示新的 深入了解AD和AD相关痴呆（ADRD）的发病机制。具体而言，这项建议旨在 揭示与血管Aβ清除和由阿帕诱导的CVD易感性相关的新途径 失去NUDT 1。这些概念在AD中尚未得到充分探讨，因此，该提案有可能 刺激额外的活动，导致AD和ADRD的进展。

Project Summary Alzheimer's disease (AD) is a severe neurodegenerative disorder of the brain that affects 35 million people in the world and 5.5 in the USA. AD is the most common form of dementia accounting for up to 56% of cases years after diagnosis. Limited therapies are available for AD and they do not delay or halt the progression of disease and thus new treatments are urgently needed. AD is characterized by the accumulation of cerebral plaques composed of amyloid-β (Aβ), which is believed to be an early pathogenic event. Most cases of AD are sporadic and develop after the age of 65 years. Recent studies have indicated an overall impairment in Aβ clearance, rather than Aβ overproduction to be critical in AD. One of the most common observations in AD, present in up to 98% of AD patients, is the presence of cerebral amyloid angiopathy (CAA). A recent study has demonstrated that vascular smooth muscle cells (VSMCs) in the brain are capable of mediating local clearance of Aβ. CAA is also a major trigger of intracranial hemorrhage a feature of cerebrovascular disease (CVD). This is significant since there is a large body of literature demonstrating a link between CVD and AD and its correlation with dementia. Despite the importance of the vasculature in AD, the link between Aβ clearance through VSMCs and increased CVD leading to dementia is not fully understood. NUDT21, also known as cleavage factor 25 (CFIm25), is an RNA binding protein that when depleted leads to alternative polyadenylation (APA) and global 3'UTR shortening. Our research on NUDT21 has revealed that depletion of NUDT21 is present in the brains of patients with AD and leads to alterations in protein transport and processing pathways in vascular smooth muscle cells (VSMCs). Our overall hypothesis is that loss of cerebral vascular smooth muscle NUDT21 disrupts Aβ clearance and predisposes the brain to CVD. This will be tested in the following Specific Aims: 1- Evaluate the role of NUDT21 loss and 3'UTR landscape in AD; 2- Determine whether NUDT21 depletion promotes CAA and 3- Assess whether NUDT21 depletion exacerbates cerebrovascular disease (CVD). Successful completion of these experiments is expected to reveal new insights into the pathogenesis of AD and AD related dementias (ADRD). Specifically, this proposal aims to uncover novel pathways related to vascular Aβ clearance and predisposition to CVD linked by APA induced by loss of NUDT1. These concepts have not been fully explored in AD thus; this proposal has the potential to stimulate additional activity leading to progress on AD and ADRD.