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）是大脑的严重神经退行性疾病，影响3500万人世界和5.5在美国。广告是痴呆症最常见的形式，最多可占病例的56％诊断后的几年。有限的疗法可用于AD，它们不会延迟或停止迫切需要疾病，因此需要新的治疗方法。 AD的特征是大脑的积累由淀粉样蛋白β（Aβ）组成的斑块，据信这是一个早期的致病事件。大多数广告案例是零星并在65岁以后发展。最近的研究表明Aβ的总体损害清除率，而不是Aβ生产对于AD至关重要。广告中最常见的观察之一，在多达98％的AD患者中，存在脑淀粉样血管病（CAA）。最近的一项研究有证明大脑中的血管平滑肌细胞（VSMC）能够介导局部间隙 Aβ。 CAA也是颅内出血的主要触发因素，一种脑血管疾病（CVD）的特征。这很重要，因为有大量的文献证明了CVD与AD之间的联系与痴呆症的相关性。尽管脉管系统在AD中很重要，但Aβ间隙之间的联系通过VSMC和CVD增加导致痴呆症。 nudt21，也称为切割因子25（CFIM25）是一种RNA结合蛋白，当耗尽会导致替代时聚腺苷酸化（APA）和全局3'UTR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（VSMC）中的处理途径。我们的总体假设是脑丧失血管平滑肌NUDT21破坏了Aβ清除率，使大脑易于CVD。这将进行测试在以下具体目的中：1-评估NUDT21损失和3'UTR景观在AD中的作用； 2-确定 NUDT21部署是否促进CAA和3-评估NUDT21部署是否加剧脑血管疾病（CVD）。这些实验的成功完成有望揭示新的对AD和AD相关痴呆症（ADRD）的发病机理的见解。具体来说，该提议旨在发现与由APA连接的血管Aβ清除率和对CVD的易感性有关的新型途径 NUDT1的损失。这些概念尚未在广告中得到充分探索。该提议有可能刺激其他活动，从而导致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.

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.

Snakes and Ladders: A Potential Therapy of Hepatocyte Growth Factor and Pigment Epithelium-derived Factor in Pulmonary Hypertension.

DOI：
10.1165/rcmb.2023-0118ed
发表时间：
2023-07
期刊：
American journal of respiratory cell and molecular biology
影响因子：
6.4
作者：
通讯作者：

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

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

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.