Dysregulation of Neuronal Guidance Cue Netrin-1 in Accelerated AAA

加速 AAA 中神经元指导线索 Netrin-1 的失调

基本信息

批准号：
8804126
负责人：
Bhama Ramkhelawon
金额：
$ 11.07万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8804126
关键词：
Abdomen Abdominal Aortic Aneurysm Accounting Address Affect Animal Model Aorta Aortic Rupture Arterial Fatty Streak Atherosclerosis Award Biocompatible Blood Vessels CCL2 gene Caliber Cells Cessation of life Chemotactic Factors Chemotaxis Clinical Collagen Conflict (Psychology)Congresses Country Cues Data Deterioration Development Development Plans Disease Disease Progression Elastin Elderly man Emigrations Encapsulated Ensure Environment Equilibrium Foam Cells Fostering Functional disorder Future Gene Expression Profiling Genes Goals Grant Head Hematopoietic Human IL6 gene Immune Incidence Individual Infiltration Inflammation Inflammatory Interleukin-10 Interleukin-4 Interleukin-6 Knowledge Label Laboratories Latex Bead Lead Life Lipids Lymphocyte Manuscripts Matrix Metalloproteinases Measures Medial Medical center Mentors Monitor Mus New York Operative Surgical Procedures Pathology Patients Pharmaceutical Preparations Phase Play Preventive Reaction Reactive Oxygen Species Recruitment Activity Regulation Research Research Personnel Research Project Grants Resolution Role Rupture Severity of illness Signal Transduction Site Small Interfering RNA Specimen Stents Supervision TNF gene Tamoxifen Techniques Testing Therapeutic Tissues Training United States Universities Up-Regulation Writing abstracting animal breeding base career career development cytokine drug development human NTN1 protein in vivo innovation insight interest laser capture microdissection macrophage mast cell migration monocyte mouse model nano-string nanomaterials nanoparticle netrin-1 neuronal guidance neutrophil novel prevent receptor repaired research study response responsible research conduct skills therapy development tissue repair trafficking

项目摘要

DESCRIPTION (provided by applicant): Abstract Dr. Bhama Ramkhelawon nourishes 2 career goals during this award. An immediate goal to gain knowledge into the expression of the neuronal guidance cue, Netrin-1 in macrophage-elicited inflammation in Abdominal Aortic Aneurysms (AAAs) and a long-term career goal to become an independent investigator capable of leading research and ascribe a possible role Netrin-1 as a novel target for development of therapies to curb the burden of AAA. AAA is characterized by a focal dilation of the aortic diameter >30 mm located in the infrarenal section of the aorta. Roughly 25,000 AAA repairs are performed each year, and despite progress in primary preventive measures, AAA still accounts for > 13,000 deaths annually in the United States. Previous histological studies have revealed that transmural inflammation is manifested by the presence of monocytes/macrophages. This inflammation is associated with the proteolytic destruction of the aortic wall through the degradation of elastin and collagen by matrix metalloproteinases (MMPs). Numerous studies have profoundly explored the mechanisms related to the proteolitic disruption of the blood vessel. To better appreciate preventive therapeutic strategies, it is crucial to understand the broad spectrum of the physiopathology. Since Mo have important roles in both the induction and resolution of inflammation, I hypothesize that in addition to signals directing their recruitment t the focal site of aortic dilation, other cues are expressed to orient the advanced avenues related to the laminal destructive capacity of these cells. We have recently demonstrated a critical role for the neuronal guidance cue, Netrin-1 in promoting atherosclerosis by blocking their chemotaxis to exit signals such as CCL-19. Interestingly, my preliminary data show that the signals (IL-6 and TNfa) that direct Mo recruitment can also induce the expression of retention cues such as Netrin-1 in both mice and clinical human AAA specimens. We propose another innovative role for Netrin-1 in orchestrating AAA-induced inflammation in a non-lipidemic environment. In this grant, we will use novel mouse models of tissue-specific or conditional deletion of Netrin-1 to determine how this guidance cue alters the dynamic regulation of Mo into AAA sites, and direct their polarization. During the mentored research phase (K99), I will complete my ongoing research projects under Dr. Moore's supervision at New York University Langone Medical Center. I will gain expertise in important aspects of Mo elicited inflammation in AAA in her laboratory. I will take the opportunity of all the facilities available at the research center to perform key experiments required to study AAA and hence specialize myself in this field. Dr. Moore will serve as Primary Mentor and oversee all aspects of my transition to become an Independent Researcher. Together we have elaborated a career development plan, which encompasses guidance in project progress, manuscript and grant writing, animal breeding, congress attendance and to perform training in the responsible conduct of research. In addition, a team of four Co-Mentors will provide me with complementary research guidance and help which will greatly enhance and diversify my research skill set. Together, the team of Mentors has pledged to guide me to extend my research interests and approaches, and to ensure a successful transition to an independent researcher. During the independent phase (R00) of this award, I will test the therapeutic avenues of silencing Netrin-1 by using nanoparticles encapsulating siRNA in the AAA mouse model. We expect to successfully dampen Mo inflammation associated with vessel wall destruction by targeting Netrin-1 in vivo. These experiments will provide key insights into promising surgery alternatives and will head toward translationally applied future drug development to treat AAA.

描述（由申请人提供）：摘要 Bhama Ramkhelawon 博士在获奖期间实现了 2 个职业目标。近期目标是了解神经元引导信号 Netrin-1 在腹主动脉瘤 (AAA) 巨噬细胞引发的炎症中的表达，长期职业目标是成为一名能够领导研究并归因于可能的独立研究人员Netrin-1 的作用作为开发抑制 AAA 负担疗法的新靶点。 AAA 的特征是位于主动脉肾下部分的主动脉直径 >30 mm 的局灶性扩张。每年大约进行 25,000 例 AAA 修复，尽管初级预防措施取得了进展，但美国每年 AAA 仍然导致超过 13,000 例死亡。先前的组织学研究表明，透壁炎症表现为单核细胞/巨噬细胞的存在。这种炎症与基质金属蛋白酶 (MMP) 降解弹性蛋白和胶原蛋白对主动脉壁的蛋白水解破坏有关。大量研究深入探讨了与血管蛋白水解破坏相关的机制。为了更好地理解预防性治疗策略，了解广泛的病理生理学至关重要。由于Mo在炎症的诱导和消退中都具有重要作用，我假设除了引导它们募集到主动脉扩张的焦点部位的信号之外，还表达其他线索来定向与这些细胞的层层破坏能力相关的高级途径。我们最近证明了神经元引导信号 Netrin-1 通过阻止其趋化性退出信号（如 CCL-19）来促进动脉粥样硬化。有趣的是，我的初步数据表明，指导 Mo 募集的信号（IL-6 和 TNfa）也可以诱导小鼠和临床人类 AAA 标本中 Netrin-1 等保留信号的表达。我们提出 Netrin-1 在非脂血症环境中协调 AAA 诱导的炎症方面的另一个创新作用。在这笔资助中，我们将使用组织特异性或条件性删除 Netrin-1 的新型小鼠模型来确定这种引导信号如何改变 Mo 对 AAA 位点的动态调节，并指导它们的极化。在指导研究阶段（K99），我将在纽约大学朗格尼医学中心摩尔博士的监督下完成我正在进行的研究项目。我将在她的实验室获得有关 Mo 引发 AAA 炎症的重要方面的专业知识。我将利用研究中心的所有可用设施进行研究 AAA 所需的关键实验，从而专注于该领域。摩尔博士将担任主要导师，并监督我向独立研究员过渡的各个方面。我们共同制定了职业发展计划，其中包括项目进展指导、手稿和拨款写作、动物育种、出席会议以及开展负责任的研究行为培训。此外，由四位联合导师组成的团队将为我提供补充性的研究指导和帮助，这将极大地增强我的研究技能并使其多样化。导师团队共同承诺指导我扩展我的研究兴趣和方法，并确保成功过渡为独立研究员。在该奖项的独立阶段 (R00) 期间，我将在 AAA 小鼠模型中使用封装 siRNA 的纳米颗粒来测试沉默 Netrin-1 的治疗途径。我们期望通过体内靶向 Netrin-1 成功抑制与血管壁破坏相关的 Mo 炎症。这些实验将为有希望的手术替代方案提供重要见解，并将推动未来治疗 AAA 药物的转化应用。