Role of Notch1 Signaling in Abdominal Aortic Aneurysm

Notch1 信号在腹主动脉瘤中的作用

基本信息

批准号：
9344678
负责人：
Chetan Hans
金额：
$ 38.2万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9344678
关键词：
Abdominal Aortic Aneurysm Acute Affect Age Age-Years Angiotensin II Anti-Inflammatory Agents Anti-inflammatory Aortic Injury Apolipoprotein E Apoptotic Attenuated Binding Biological Assay Blood Vessels Bone Marrow Transplantation Cause of Death Cell Culture Techniques Cells Cessation of life Chronic Communicable Diseases Complication Data Development Diagnostic Procedure Disease Economic Burden Equilibrium Expenditure Gene Targeting Goals Growth Health Human Impairment Incidence Individual Infiltration Inflammation Inflammatory Inflammatory Response Infusion procedures Injury Intervention Investigation Knock-out Knockout Mice Life Link Literature Luciferases Mediating Mission Molecular Mus Mutant Strains Mice Myelogenous Operative Surgical Procedures Pathogenesis Patients Periodicity Phagocytes Pharmacology Phenotype Population Prevalence Prevention Production Public Health Publishing Regulation Reporting Research Resolution Risk Role Running Rupture Series Signal Transduction Societies Stimulus Testing Therapeutic Time Tissues Transforming Growth Factor Beta 2 Transforming Growth Factor alpha United States National Institutes of Health Up-Regulation Vascular Diseases abdominal aorta base cell injury cell type chemokine chromatin immunoprecipitation clinically relevant cost effective cytokine design economic impact effective therapy experimental study gain of function improved innovation insight loss of function macrophage male monocyte mouse model notch protein novel novel drug class novel therapeutic intervention prevent promoter protective effect public health relevance repaired response time interval tissue repair tool transcription factor treatment strategy

Abdominal Aortic Aneurysm Acute Affect Age Age-Years Angiotensin II Anti-Inflammatory Agents Anti-inflammatory Aortic Injury Apolipoprotein E Apoptotic Attenuated Binding Biological Assay Blood Vessels Bone Marrow Transplantation Cause of Death Cell Culture Techniques Cells Cessation of life Chronic Communicable Diseases Complication Data Development Diagnostic Procedure Disease Economic Burden Equilibrium Expenditure Gene Targeting Goals Growth Health Human Impairment Incidence Individual Infiltration Inflammation Inflammatory Inflammatory Response Infusion procedures Injury Intervention Investigation Knock-out Knockout Mice Life Link Literature Luciferases Mediating Mission Molecular Mus Mutant Strains Mice Myelogenous Operative Surgical Procedures Pathogenesis Patients Periodicity Phagocytes Pharmacology Phenotype Population Prevalence Prevention Production Public Health Publishing Regulation Reporting Research Resolution Risk Role Running Rupture Series Signal Transduction Societies Stimulus Testing Therapeutic Time Tissues Transforming Growth Factor Beta 2 Transforming Growth Factor alpha United States National Institutes of Health Up-Regulation Vascular Diseases abdominal aorta base cell injury cell type chemokine chromatin immunoprecipitation clinically relevant cost effective cytokine design economic impact effective therapy experimental study gain of function improved innovation insight loss of function macrophage male monocyte mouse model notch protein novel novel drug class novel therapeutic intervention prevent promoter protective effect public health relevance repaired response time interval tissue repair tool transcription factor treatment strategy

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项目摘要

DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) is a progressive enlargement of the abdominal aorta with a prevalence of ~9% in the male population of age 65 years and above. The disease accounts for over 15,000 deaths each year in the US alone. Moreover, the only treatment option for AAA is surgical intervention, which comes with an associated financial burden. With 25,000 surgical repairs occurring in the US annually, the total expenditure runs into billions of dollars thus impacting economic burden of the society. Only with an increased understanding of the mechanism(s) underlying the development of AAA will novel non- surgical therapies be devised to reduce AAA progression. While multiple factors are involved in disease pathogenesis, the critical stimulus is the differentiation and infiltration of naïve macrophages (Mf). A typical response to aortic injury elicits differentiation of a classic M form of macrophages from Mf, which produce high levels of pro-inflammatory cytokines and chemokines to phagocytize apoptotic cells and damage- associated debris. However, their uncontrolled production damages the healthy tissue leading to aortic dilation and death of vascular cells. In contrast, Mfs have also the potential to be programmed to an alternative differentiation termed M2-like macrophages. These M2 macrophages have the ability to inhibit the inflammatory response and promote tissue repair. Although the roles of pro-inflammatory M1 macrophages have been well characterized in various vascular diseases including AAA, little is known about the critical factors that initiate the differentiation of Mf into M2-phenotyp and their potential roles in AAA. Our lab has recently identified Notch1 as one such which factor promotes M2-differentiation of Mf. The long term goal of our research is to determine the roles for M2-differentiated macrophages in vascular diseases. The objective of this proposal is to determine if Notch1 deficiency in macrophages prevents AAA progression by increasing M2 differentiation of Mf. Based upon our preliminary studies and published literature, we hypothesize that deficiency of Notch1 will increase differentiation of Mf into M2-phenotype by TGF-ß2 dependent mechanisms. We plan to test our hypotheses with the following Specific Aims: i) Determine if myeloid-specific inducible- Notch1 haploinsufficiency can prevent AAA progression; ii) Determine if M2-differentiated macrophages protect against AAA development in mice and iii) Determine if TGF-ß2 is a critical requirement for Notch1-mediated M2 differentiation of Mf. These Specific Aims are designed to provide a comprehensive assessment of the regulatory role of Notch1 signaling on M2 differentiation of Mf in the setting of AAA. Our approach is innovative as we are proposing a series of experiments using double mutant mice generated in the lab, cell culture and human aortae obtained from AAA patients to achieve our goal. The proposed research is highly significant because it may provide the necessary steps for the therapeutic application targeting Notch1 to increase M2 population of macrophages for the prevention of AAA growth.

描述（由适用提供）：腹主动脉瘤（AAA）是腹主动脉的逐渐增加，在65岁及以上的男性人口中的患病率为约9％。仅在美国，该疾病每年就会造成15,000多人死亡。此外，AAA的唯一治疗选择是外科干预，这与相关的金融伯恩（Burnen）随附。每年在美国进行25,000次手术维修，总支出达到了数十亿美元，从而影响了社会的经济燃烧。只有对AAA发展的基础机制的理解越来越多，才能设计出新型的非手术疗法以减少AAA进展。尽管疾病发病机理涉及多个因素，但关键刺激是幼稚巨噬细胞（MF）的分化和渗透。对主动脉损伤的典型反应引起了经典M形式的巨噬细胞与MF的分化，MF产生高水平的促炎性细胞因子和趋化因子，以吞噬凋亡细胞和损伤相关的碎屑。但是，它们不受控制的产生会损害导致主动脉词典和血管细胞死亡的健康组织。相比之下，MF还具有编程到称为M2样巨噬细胞的替代分化的潜力。这些M2巨噬细胞具有抑制炎症反应的能力，尽管促炎性M1巨噬细胞的作用在包括AAA在内的各种血管疾病中的表征都很好，但对引发MF分化为M2-杂种型的关键因素鲜为人知，但对M2-PheNotyp及其在AAA中的潜在启动的关键因素却几乎没有。我们的实验室最近将Notch1确定为这样的因素，促进了MF的M2差异。我们研究的长期目标是确定M2差异巨噬细胞在血管疾病中的作用。该提案的目的是确定巨噬细胞中的Notch1缺乏是否通过增加M2的M2分化来阻止AAA进展。基于我们的初步研究和发表的文献，我们假设Notch1的缺乏将通过TGF-Eβ依赖机制增加MF分化为M2-型。我们计划以以下特定目的测试我们的假设：i）确定髓样特异性诱导 - notch1单倍不足可以防止AAA的进展； ii）确定M2分化的巨噬细胞是否可以预防小鼠的AAA发育和iii）确定TGF-ß2是否是Notch1介导的M2分化MF的关键要求。这些具体目的旨在对Notch1信号在AAA的M2分化中的调节作用进行全面评估。我们的方法具有创新性，因为我们提出了一系列实验，使用实验室，细胞培养和人主动脉从AAA患者获得的双重突变小鼠以实现我们的目标。拟议的研究非常重要，因为它可能为针对Notch1的治疗应用提供必要的步骤，以增加巨噬细胞的M2种群以防止AAA增长。