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3'UTR Shortening In Pulmonary Vascular Disease

肺血管疾病中的 3UTR 缩短

基本信息

批准号：
10285407
负责人：
Harry Karmouty-Quintana
金额：
$ 34.08万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10285407
关键词：
3&apos Untranslated Regions Abeta clearance Accounting Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyloid beta-Protein Arteries Blood Vessels Brain Brain Diseases Cerebral Amyloid Angiopathy Cerebral cortex Cerebrovascular Disorders Cerebrovascular system Cerebrum Cessation of life Data Dementia Deposition Diagnosis Disease Progression Drainage procedure Event Experimental Models Failure Genes Impairment In Vitro Intercellular Fluid Intracranial Hemorrhages Ischemic Stroke LDL-Receptor Related Protein 1 Lead Leptomeninges Libraries Link Literature Lung Mediating Memory Loss Memory impairment Mus Neurodegenerative Disorders Neurological outcome Pathogenesis Pathogenicity Pathology Pathway interactions Patients Polyadenylation Predisposition RNA-Binding Proteins Research Risk Factors Role Senile Plaques Smooth Muscle Actin Staining Method Smooth Muscle Myocytes Testing Vascular Diseases Vascular Smooth Muscle Vascular remodeling abeta accumulation abeta deposition amyloid formation arteriole brain tissue cerebrovascular cleavage factor cognitive function effective therapy experimental study extracellular in vivo insight long term memory neurofibrillary tangle formation novel pre-clinical protein transport stroke outcome transcriptome sequencing vascular smooth muscle cell proliferation

项目摘要

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.

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VSMC和心血管疾病增加导致痴呆症的原因尚未完全了解。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。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Emerging Mechanisms of Pulmonary Vasoconstriction in SARS-CoV-2-Induced Acute Respiratory Distress Syndrome (ARDS) and Potential Therapeutic Targets.

DOI：
10.3390/ijms21218081
发表时间：
2020-10-29
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Karmouty-Quintana H;Thandavarayan RA;Keller SP;Sahay S;Pandit LM;Akkanti B
通讯作者：
Akkanti B

Cleavage stimulating factor 64 depletion mitigates cardiac fibrosis through alternative polyadenylation.

裂解刺激因子64耗竭可通过替代聚腺苷酸化来减轻心脏纤维化。

DOI：
10.1016/j.bbrc.2022.01.093
发表时间：
2022-03-15
期刊：
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
影响因子：
3.1
作者：
Neupane, Rahul;Youker, Keith;Yalamanchili, Hari Krishna;Cieslik, Katarzyna A.;Karmouty-quintana, Harry;Guha, Ashrith;Thandavarayan, Rajarajan A.
通讯作者：
Thandavarayan, Rajarajan A.

Hyaluronan in the pathogenesis of acute and post-acute COVID-19 infection.

透明质酸在急性和急性后共证感染的发病机理中。

DOI：
10.1016/j.matbio.2023.02.001
发表时间：
2023-03
期刊：
MATRIX BIOLOGY
影响因子：
6.9
作者：
Barnes, Henry W.;Demirdjian, Sally;Haddock, Naomi L.;Kaber, Gernot;Martinez, Hunter A.;Nagy, Nadine;Karmouty-Quintana, Harry;Bollyky, Paul L.
通讯作者：
Bollyky, Paul L.

Implication of Ventricular Assist Devices in Extracorporeal Membranous Oxygenation Patients Listed for Heart Transplantation.

心室辅助装置对接受心脏移植的体外膜氧合患者的影响。

DOI：
10.3390/jcm8050572
发表时间：
2019
期刊：
Journal of clinical medicine
影响因子：
3.9
作者：
Guha,Ashrith;Hannawi,Bashar;Cruz-Solbes,AnaS;Nguyen,DucT;Bruckner,BrianA;Trachtenberg,Barry;Graviss,EdwardA;Bhimaraj,Arvind;Park,Myung;Hussain,Imad;MacGillivray,ThomasE;Suarez,ErikE;Estep,JerryD
通讯作者：
Estep,JerryD

Crystal Deposits in Macrophages and Distal Lung Remodeling: A Tale of Aging in SFTPC-Deficient Mice.

巨噬细胞中的晶体沉积和远端肺重塑：SFTPC 缺陷小鼠的衰老故事。