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: 8974440
• 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
• 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/8974440
• 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; 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; Tissues; Training; United States; Universities; Up-Regulation; Writing; abstracting; animal breeding; base; career; career development; cytokine; drug development; histological studies; in vivo; innovation; insight; interest; laser capture microdissection; macrophage; migration; monocyte; mouse model; nano-string; nanomaterials; nanoparticle; neuronal guidance; neutrophil; novel; prevent; receptor; repaired; research study; response; responsible research conduct; skills; therapy development; tissue repair; trafficking

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）：摘要博士巴玛Ramkhelawon在此期间授予2个职业目标。近期目标是了解神经元引导因子Netrin-1在腹主动脉瘤（AAA）巨噬细胞引起的炎症中的表达，长期职业目标是成为能够领导研究的独立研究者，并将Netrin-1作为开发治疗的新靶点，以抑制AAA的负担。AAA的特征在于位于主动脉肾下段的主动脉直径>30 mm的局灶性扩张。每年大约进行25，000例AAA修复，尽管在初级预防措施方面取得了进展，但在美国每年仍有超过13，000例AAA死亡。先前的组织学研究表明，透壁性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）通过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。许多研究已经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，了解广泛的生理病理学至关重要。由于Mo在炎症的诱导和消退中具有重要作用，我推测除了指示它们在主动脉扩张的焦点部位的募集的信号之外，还表达了其他线索以定向与这些细胞的层破坏能力相关的高级途径。我们最近已经证明了神经元引导因子Netrin-1通过阻断其趋化性以退出信号（如CCL-19）而在促进动脉粥样硬化中的关键作用。有趣的是，我的初步数据显示，直接Mo募集的信号（IL-6和TNfa）也可以诱导小鼠和临床人AAA标本中的滞留线索（如Netrin-1）的表达。我们提出Netrin-1在非流行性环境中协调AAA诱导的炎症中的另一个创新作用。在这项研究中，我们将使用组织特异性或条件性缺失Netrin-1的新型小鼠模型来确定这种指导线索如何改变Mo到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的摩尔博士的监督下完成我正在进行的研究项目。我将在她的实验室中获得Mo引起AAA炎症的重要方面的专业知识。我将利用研究中心的所有设施进行研究AAA所需的关键实验，从而使自己专注于这一领域。 摩尔博士将担任主要导师，并监督我转变为独立研究员的各个方面。我们共同制定了一个职业发展计划，其中包括项目进展，手稿和赠款写作，动物饲养，会议出席指导，并在负责任的研究行为进行培训。此外，一个由四名共同导师组成的团队将为我提供补充性的研究指导和帮助，这将大大提高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，并确保成功过渡到独立研究人员。 在该奖项的独立阶段（R 00），我将通过在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。我们期望通过在体内靶向Netrin-1成功地抑制与血管壁破坏相关的Mo炎症。这些实验将为有前景的手术替代方案提供关键见解，并将朝着预防性应用的未来药物开发方向发展，以治疗AAA。