3'UTR Shortening In Pulmonary Vascular Disease

项目摘要 阿尔茨海默病(AD)是一种严重的大脑神经退行性疾病，在美国有3500万人受到影响 世界和美国分别为5.5和5.5。AD是最常见的痴呆症形式，占痴呆症病例的56% 在确诊数年后。阿尔茨海默病的治疗方法有限，它们不会延缓或阻止AD的进展 因此迫切需要新的治疗方法。AD的特点是脑积聚 斑块由淀粉样蛋白-β(Aβ)组成，被认为是一种早期致病事件。大多数AD病例是 散发性，65岁以后发展。最近的研究表明，β的整体损害 在AD中，关键是清理，而不是β生产过剩。在AD中最常见的观察之一， 高达98%的AD患者存在脑淀粉样血管病变(CAA)。最近的一项研究表明 证明大脑中的血管平滑肌细胞(VSMCs)能够介导局部清除 一个β的人。CAA也是脑血管疾病(CVD)的特征之一--颅内出血的主要诱因。这 意义重大，因为有大量文献表明心血管疾病和AD之间的联系，以及 与痴呆症的相关性。尽管血管系统在AD中很重要，但β清除之间的联系 通过VSMCs和增加的CVD导致痴呆的机制还不完全清楚。NUDT21，也称为 裂解因子25(CFIm25)是一种RNA结合蛋白，当耗尽时会导致替代 多聚腺苷酸化(APA)和全球3‘非编码区缩短。我们对NUDT21的研究表明， NUDT21存在于AD患者的大脑中，并导致蛋白质转运和 血管平滑肌细胞(VSMCs)的加工途径。我们的总体假设是大脑的丧失 血管平滑肌NUDT21破坏β清除，使大脑易患脑血管病。这将会被测试 在以下具体目标中：1-评估NUDT21丢失和3‘UTR景观在AD中的作用；2-确定 NUDT21枯竭是否促进CAA和3-评估NUDT21枯竭是否加剧 脑血管疾病(CVD)。这些实验的成功完成有望揭示出新的 对AD和AD相关痴呆(ADRD)发病机制的洞察。具体地说，这项建议旨在 发现与血管Aβ清除相关的新途径和与APA相关的心血管疾病易感性 失去NUDT1。因此，这些概念在AD中还没有得到充分的探讨；本提案有可能 刺激额外的活动，从而在AD和ADRD方面取得进展。

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.