Dysregulation of Neuronal Guidance Cue Netrin-1 in Accelerated AAA

Bhama Ramkhelawon博士在这一奖项中滋养了两个职业目标。眼前要达到的目标 对神经元引导信号Netrin-1在巨噬细胞诱导的炎症中的表达的认识 腹主动脉瘤(AAA)和成为一名独立调查员的长期职业目标 有能力领导 研究Netrin-1作为新的治疗靶点的可能作用 以遏制AAA的负担。AAA的特征是主动脉直径局灶性扩张<30 mm，位于 大动脉的肾下段。每年大约进行25,000次AAA修复，尽管取得了进展 在初级预防措施中，AAA每年在美国仍造成13,000例死亡。上一首 组织学研究表明，穿壁性炎症表现为 单核/巨噬细胞。这种炎症与主动脉壁的蛋白分解破坏有关。 通过基质金属蛋白酶(MMPs)降解弹性蛋白和胶原。许多研究都有 深入探讨了与蛋白质组化性血管破坏相关的机制。为了更好地 欣赏预防性治疗策略，了解广泛的 生理病理学。由于摩尔在炎症的诱导和消退中都起着重要的作用，即 假设除了引导它们重新聚集到主动脉扩张的焦点部位的信号外，其他线索 表达是为了引导与这些细胞的椎板破坏能力相关的高级途径。我们 最近证实了神经元引导信号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退出信号，如CCL-19。有趣的是，我的初步数据显示 信号(IL-6和TNFa)的直接重新募集也可以诱导保留线索的表达，如 小鼠和临床人类AAA标本中的Netrin-1。我们建议Netrin-1在 在非血脂环境中协调AAA引起的炎症。在这笔赠款中，我们将使用新颖的鼠标 组织特异性或有条件删除Netrin-1的模型，以确定该指导线索如何改变 动态调节Mø进入AAA位点，并引导它们的极化。 在指导研究阶段(K99)，我将在博士的指导下完成我正在进行的研究项目。 摩尔在纽约大学朗格尼医疗中心的监督。我将在重要方面获得专业知识 在她的实验室里，一种名为莫尔的药物引起了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，因此我专门从事这一领域的工作。 摩尔博士将担任首席导师，监督我过渡到成为一名 独立研究人员。我们共同制定了一项职业发展计划，其中包括 指导项目进展、手稿和赠款的撰写、动物饲养、出席大会和 进行负责任的研究行为培训。此外，一个由四名共同导师组成的团队将为我提供 辅以研究指导和帮助，这将极大地增强和多样化我的研究技能。 导师团队共同承诺引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(R00)，我将测试沉默的治疗途径 在AAA小鼠模型中通过使用包裹siRNA的纳米颗粒来实现netrin-1。我们期待着成功 通过体内靶向Netrin-1抑制与血管壁破坏相关的摩尔炎症。这些 实验将提供对有前景的手术替代方案的关键见解，并将朝着翻译的方向发展 应用未来的药物开发来治疗AAA。

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.