Vascular Targeting Genomic & Genetic Strategies for Acute Chest Syndrome

血管靶向基因组

• 批准号: 10674112
• 负责人: Roberto F. Machado
• 金额: $ 75.33万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-05 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674112
• 关键词: Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Admission activity; Biogenesis; Biological Markers; Blood Vessels; CDKN1A gene; Cause of Death; Cell Adhesion Molecules; Cessation of life; Chronic; Critical Pathways; Development; Endothelial Cells; Endothelium; Erythrocytes; Funding; Genes; Genetic; Genetic Markers; Genomic approach; Genomics; Hospitalization; Hour; Hypoxia; Impairment; Individual; Inflammatory; Inflammatory Response; Lipids; Lung; Molecular Target; Morbidity - disease rate; Mus; Pathway interactions; Patient Care; Patients; Physicians; Predisposition; Ras Signaling Pathway; Resistance; Risk; Risk Factors; Role; Scientist; Severities; Sickle Cell Anemia; Syndrome; Systems Biology; T-cell receptor repertoire; Testing; Therapeutic; Time; acute chest syndrome; beta Chain Antigen T Cell Receptor; career; clinical care; diacylglycerol O-acyltransferase; genetic approach; health disparity; improved; insight; lung injury; meter; molecular marker; mortality; novel; novel strategies; premature; pulmonary vascular disorder; response; therapeutic target; tool; translational approach; translational study

ABSTRACT The PI of this application is a physician-scientists with a career focus on developing improved care for patients with sickle cell disease (SCD). The acute chest syndrome (ACS) represents a serious, potentially fatal inflammatory lung injury syndrome occurring in patients with SCD. ACS shares many features of the inflammatory lung injury associated with acute lung injury and is the second most common cause of SCD hospitalization, is a major cause of acute and chronic SCD morbidity and mortality, is the leading cause of SCD ICU admission and premature death. There is increasing appreciation that ACS is an acute hypoxia-induced lung injury syndrome targeting the lung endothelium in response to multiple exogenous insults or triggers leading to pulmonary erythrocyte sequestration, an exaggerated inflammatory response, increased expression of adhesion molecules and impairment of pulmonary vascular function. In this highly translational proposal we will address the hypothesis that vascular-targeted genetic and genomic strategies for ACS will lead to better understanding of the pathobiology of ACS, generate novel ACS biomarkers in SCD patients and produce vascular-specific therapies for ameliorating this devastating health disparity. To address this hypothesis, in Specific Aim #1 we will test and validate the potential of T-cell receptor repertoire profiling as modifiers and biomarkers of ACS susceptibility. Specific Aim #2 will interrogate the role of RASA3 as a molecular target in murine ACS. In Specific Aim #3 we will interrogate the role of endothelial cell lipid droplets as a molecular and therapeutic target in murine ACS. Together, these highly translational approaches hold the promise to identify novel targets and biomarkers that may lead to better treatment options for patients with ACS.

摘要 该应用程序的PI是一名医生-科学家，其职业重点是为患者开发更好的护理 镰状细胞病（SCD）急性胸部综合征（ACS）是一种严重的，可能致命的疾病。 SCD患者发生炎性肺损伤综合征。ACS与 炎性肺损伤与急性肺损伤相关，是SCD的第二大常见原因 住院治疗是导致急性和慢性SCD发病率和死亡率的主要原因，是SCD的主要原因 ICU入院和过早死亡。越来越多的人认识到ACS是一种急性缺氧诱导的 靶向肺内皮细胞的肺损伤综合征对多种外源性损伤或触发物的反应 导致肺部红细胞隔离，过度的炎症反应， 粘附分子和肺血管功能受损。在这个高度翻译的建议中，我们 将解决这一假设，即针对ACS的血管靶向遗传和基因组策略将导致更好的 了解ACS的病理生物学，在SCD患者中产生新的ACS生物标志物， 血管特异性疗法来改善这种毁灭性的健康差异。为了解决这个问题，在 具体目标#1我们将测试和验证T细胞受体库谱作为修饰剂的潜力， ACS易感性的生物标志物。具体目标#2将询问RASA 3作为分子靶标在以下方面的作用： 鼠ACS。在具体目标#3中，我们将探讨内皮细胞脂滴作为分子和细胞因子的作用。 小鼠ACS的治疗靶点。总之，这些高度转化的方法有望识别 新的靶点和生物标志物可能为ACS患者带来更好的治疗选择。

项目成果

Pharmacologic treatments for pulmonary hypertension: exploring pharmacogenomics.

肺动脉高压的药理治疗：探索药物基因组学。

• DOI: 10.2217/fca.13.6
• 发表时间: 2013-05
• 期刊: Future cardiology
• 影响因子: 1.7
• 作者: Duarte JD;Hanson RL;Machado RF
• 通讯作者: Machado RF

High sodium causes hypertension: evidence from clinical trials and animal experiments.

• DOI: 10.1016/s2095-4964(15)60155-8
• 发表时间: 2015
• 期刊: Journal of integrative medicine
• 作者: V. Reddy;A. Sridhar;R. Machado;Jiwang Chen

Vascular complications of sickle cell disease.

镰状细胞病的血管并发症。

• DOI: 10.3233/ch-189008
• 发表时间: 2018
• 期刊: Clinical hemorheology and microcirculation
• 影响因子: 2.1
• 作者: Usmani,Ashar;Machado,RobertoF
• 通讯作者: Machado,RobertoF

Nontuberculous mycobacterial disease mortality in the United States, 1999-2010: a population-based comparative study.

• DOI: 10.1371/journal.pone.0091879
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Mirsaeidi M;Machado RF;Garcia JG;Schraufnagel DE
• 通讯作者: Schraufnagel DE

ARTS: automated randomization of multiple traits for study design.

ARTS：用于研究设计的多个性状的自动随机化。

• DOI: 10.1093/bioinformatics/btu075
• 发表时间: 2014
• 期刊: Bioinformatics (Oxford, England)
• 作者: Maienschein-Cline,Mark;Lei,Zhengdeng;Gardeux,Vincent;Abbasi,Taimur;Machado,RobertoF;Gordeuk,Victor;Desai,AnkitA;Saraf,Santosh;Bahroos,Neil;Lussier,Yves
• 通讯作者: Lussier,Yves