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

• 批准号: 9376989
• 负责人: Bhama Ramkhelawon
• 金额: $ 24.9万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9376989
• 关键词: Abdomen; Abdominal Aortic Aneurysm; Address; Affect; Animal Model; Aorta; Aortic Diseases; Aortic Rupture; Arterial Fatty Streak; Atherosclerosis; Award; 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; Injectable; Interleukin-10; Interleukin-4; Interleukin-6; Knowledge; Label; Laboratories; Latex Bead; Lead; Life; Lipids; Lymphocyte; Manuscripts; Matrix Metalloproteinases; Medial; Medical center; Mentors; Monitor; Mus; NTN1 gene; New York; Operative Surgical Procedures; Pathology; Patients; Pharmacotherapy; Phase; Play; Preventive; Preventive measure; 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; Thinness; Tissue Model; Tissues; Training; United States; Universities; Up-Regulation; Writing; animal breeding; base; biomaterial compatibility; career; career development; cytokine; drug development; experimental study; histological studies; in vivo; innovation; insight; interest; laser capture microdissection; macrophage; mast cell; migration; monocyte; mouse model; nano-string; nanomaterials; nanoparticle; neuronal guidance; neutrophil; novel; prevent; receptor; repaired; response; responsible research conduct; skills; therapeutic evaluation; therapy development; tissue repair; trafficking

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 Mø have important roles in both the induction and resolution of inflammation, I hypothesize that in addition to signals directing their recruitment to 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 Mø 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 Mø 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 Mø 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 Mø 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.

Bhama Ramkhelawon博士在此奖项期间实现了2个职业目标。一个直接的目标是获得 神经元导向因子Netrin-1在巨噬细胞引起的炎症中表达的知识， 腹主动脉瘤（AAA）和成为独立研究者的长期职业目标 能力领导 研究并将Netrin-1作为开发治疗方法的新靶点 以减轻AAA的负担。AAA的特征在于主动脉直径>30 mm的局灶性扩张，位于 主动脉的肾下部分每年大约有25，000例AAA修复，尽管取得了进展， 在一级预防措施中，美国每年仍有超过13，000人死于AAA。先前 组织学研究显示透壁性炎症表现为 单核细胞/巨噬细胞。这种炎症与主动脉壁的蛋白水解破坏有关 通过基质金属蛋白酶（MMP）降解弹性蛋白和胶原蛋白。大量研究 深入探讨了与血管蛋白水解破坏有关的机制。更好地 了解预防性治疗策略，至关重要的是要了解广泛的 生理病理学由于MMPs在炎症的诱导和消退中起重要作用， 假设除了将它们募集到主动脉扩张的病灶部位的信号外， 被表达以定向与这些细胞的层破坏能力相关的高级途径。我们 最近证明了神经元引导因子Netrin-1在促进动脉粥样硬化中的关键作用 通过阻断它们的趋化性来释放信号，如CCL-19。有趣的是，我的初步数据显示， 引导MMPs募集的信号（IL-6和TNfa）也可以诱导保留线索的表达， Netrin-1在小鼠和临床人AAA标本中的表达。我们提出Netrin-1在以下方面的另一个创新作用： 在非流行性环境中协调AAA诱导的炎症。在这次资助中，我们将使用新型鼠标 Netrin-1的组织特异性或条件性缺失的模型，以确定这种指导线索如何改变 动态调节Mc进入AAA位点，并引导其极化。 在指导研究阶段（K99），我将完成我正在进行的研究项目博士。 摩尔在纽约大学朗格尼医学中心的监督。我将获得重要方面的专业知识 在她的实验室中，1000 μ g的吗啡引起了AAA的炎症。我将利用所有可用的设施， 研究中心进行研究AAA所需的关键实验，因此专门从事这一领域。 博士摩尔将担任主要导师，并监督我的过渡到成为一个 独立研究员。我们共同制定了职业发展计划，其中包括 指导项目进展，手稿和赠款写作，动物育种，会议出席和 在负责任的研究行为方面进行培训。此外，一个由四名共同导师组成的团队将为我提供 与互补的研究指导和帮助，这将大大提高和多样化我的研究技能。 导师团队共同承诺指导我扩展我的研究兴趣和方法， 以确保成功过渡到独立研究人员。 在这个奖项的独立阶段（R 00），我将测试沉默的治疗途径 Netrin-1通过在AAA小鼠模型中使用包封siRNA的纳米颗粒。我们希望成功地 通过在体内靶向Netrin-1抑制与血管壁破坏相关的二尖瓣炎症。这些 实验将为有前途的手术替代方案提供关键的见解，并将朝着预防性方向发展。 应用未来的药物开发来治疗AAA。