Macrophages and Treatment-Resistant NVAMD

巨噬细胞和难治性 NVAMD

• 批准号: 9266416
• 负责人: Priyatham Sai Mettu
• 金额: $ 15.29万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266416
• 关键词: Address; Adoptive Transfer; Advisory Committees; Affect; Age related macular degeneration; Area; Award; Basic Science; Biological Assay; Biological Markers; Biology; Blindness; Blood; Blood Vessels; Blood capillaries; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium-Binding Proteins; Calcium/calmodulin-dependent protein kinase; Calmodulin; Cancer Biology; Cells; Choroidal Neovascularization; Clinical; Clinical Research; Clinical Sciences; Data; Development; Disease; Elderly; Environment; Exhibits; Experimental Models; Exposure to; Exudative age-related macular degeneration; Fellowship; Fibrosis; Foundations; Frequencies; Funding; Goals; Growth Factor; Hemorrhage; Immunology; Infection; Kinetics; Knockout Mice; Knowledge; Laboratories; Lasers; Lipopolysaccharides; Macrophage Activation; Macular degeneration; Mediating; Medicine; Mentors; Mentorship; Microscopy; Modeling; Molecular; Molecular Biology; Morphology; Mus; Muscle Cells; Myofibroblast; Ophthalmology; Outcome; PTPRC gene; Pathway interactions; Patient Care; Patients; Pattern; Perivascular Fibrosis; Pharmaceutical Preparations; Phosphotransferases; Positioning Attribute; Production; Program Development; Publications; Recruitment Activity; Regulation; Research; Research Project Grants; Resistance; Resources; Retina; Risk; Role; SECTM1 gene; Scientist; Signal Transduction; Testing; Tissues; Toxic Shock Syndrome Toxin-1; Training; Treatment Factor; United States National Institutes of Health; Vascular Endothelial Growth Factors; Vascular Smooth Muscle; Vision; Work; Zymosan; angiogenesis; arteriole; base; cancer pharmacology; capillary; career; career development; fighting; improved; innovation; knock-down; macrophage; matrigel; meetings; monocyte; mouse model; neglect; neovascular; neovascularization; novel; pathogen; prevent; public health relevance; receptor; responsible research conduct; targeted treatment; therapeutic target; translational research program

 DESCRIPTION (provided by applicant): The candidate is a retina clinician-scientist whose primary career goal is to advance the care of patients with age-related macular degeneration (AMD) by (1) elucidating disease mechanisms, with a specific focus on macrophages; and (2) identifying novel disease biomarkers and targets for therapy. In addition to clinical training, he has completed a clinical research fellowship and has spent two years in a Departmental K12 Career Development Program. In the first year, he rotated through various laboratories and in the second year, he has pursued a novel project investigating the role of activated macrophages in neovascular remodeling (NVR), the transformation of nascent capillaries into branching arterioles with perivascular fibrosis, and a major cause of treatment-resistant neovascular AMD (NVAMD). His immediate career development goals in the current proposal are to further understanding of NVR pathobiology by identifying the specific blood monocyte subset(s) that give rise to NVR-promoting macrophages and by characterizing mechanisms that regulate macrophage effector function in the setting of NVR. The candidate plans an R01 submission in early year three on an innovative translational project to characterize the biology of macrophage-mediated NVR in experimental CNV and NVAMD, correlating monocyte subset frequencies and activation states with CNV morphology and treatment-resistant NVAMD. Additional didactic training in immunology, molecular biology, microscopy, departmental research seminars, and advanced responsible conduct of research will be obtained during the award period, and the candidate will present his findings at national meetings and submit his work for publication. Environment: The mentorship and expertise of the advisory committee, the extensive resources of the Duke Departments of Ophthalmology and Pharmacology / Cancer Biology, and the significant institutional commitment will provide the support needed for this candidate to complete the proposed research project and transition successfully to an independent research career. Research: Although intravitreal anti-VEGF therapies have improved vision outcomes, 40-50% of patients exhibit treatment-resistant NVAMD / PDA. PDA occurs more frequently in patients with CNV morphology that reflects NVR. The candidate and his primary mentor have established macrophages as a driver of NVR, and preliminary data suggests that low-grade systemic exposure to three different pathogen-associated molecular patterns (PAMPs) promotes NVR in a murine model of laser-induced CNV. In spite of each PAMP having a distinct activating receptor, all three PAMP-activated signaling cascades are known to mobilize calcium and activate the calcium-binding protein, calmodulin. Accordingly, preliminary data suggests that mice null for calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), an intermediate kinase known to amplify PAMP-activated effector pathways in macrophages, demonstrate reduced NVR. The central hypothesis is that PAMP-stimulation regulates NVR through activation of CaMKK2-mediated macrophage effector function. Specifically, low-grade PAMP stimulation is hypothesized to (1) increase the frequency of circulating nonclassical Ly6Clo monocytes in blood; and (2) promotes activation of Ly6Clo monocyte-derived macrophages, increasing expression of fibrogenic growth factors, (3) via activation of CaMKK2 signaling (Fig. 2). Fibrogenic factors recruit and activate vascular smooth muscle cells and myofibroblasts, leading to development of NVR. Aim 1 will address the hypothesis that PAMP-stimulated NVR in experimental neovascularization is mediated by activated macrophages arising from nonclassical Ly6Clo blood monocytes. Aim 2 will address the hypothesis that CaMKK2 regulates macrophage-mediated NVR.

 描述（由适用提供）：候选人是视网膜临床科学家，其主要职业目标是通过（1）阐明疾病机制来推动与年龄相关的黄斑变性（AMD）的患者的护理，并特别关注巨噬细胞； （2）识别新型疾病生物标志物和治疗靶标。除临床培训外，他还完成了临床研究奖学金，并在部门K12职业发展计划中度过了两年。在第一年，他旋转了各种实验室，第二年，他追求了一个新颖的项目，调查了活化巨噬细胞在新生血管重塑（NVR）中的作用，将新生毛细血管转化为血管性纤维化的分支小动脉，并引起了治疗的耐药性Neoviscular Amd（NVamd）。他在当前建议中的直接职业发展目标是通过确定引起NVR促进巨噬细胞的特定血液单核细胞子集并表征调节NVR环境中巨噬细胞效应子功能的机制，从而进一步了解NVR病理生物学。候选人计划在第三年初提交R01提交，以创新的翻译项目为特征，以表征实验CNV和NVAMD中巨噬细胞介导的NVR的生物学，将单核细胞子集的频率和激活状态与CNV形态和治疗耐药的NVAMD相关。免疫学，分子生物学，显微镜，部门研究中心和高级负责任的研究中的其他教学培训将在奖励期内获得，候选人将在国家会议上提出他的发现，并提交其发表工作。环境：咨询委员会的心态和专家，眼科和药理学 /癌症生物学的杜克大学的广泛资源以及重大的机构承诺将为该候选人提供成功完成拟议的研究项目和过渡到独立研究职业所需的支持。研究：尽管玻璃体内抗VEGF疗法改善了视力结果，但40-50％的患者展示了耐药的NVAMD / PDA。 PDA发生在反映NVR的CNV形态患者中。候选人及其主要的心态已成为NVR的驱动力，并且初步数据表明，在激光诱导的CNV的鼠模型中，低度全身暴露于三种不同的病原体相关分子模式（PAMP）促进NVR。尽管每个PAMP都具有独特的激活受体，但已知所有三个PAMP激活的信号传导级联反应都动员钙并激活钙结合蛋白Calmolin。根据以下内容，初步数据表明，钙/钙调蛋白依赖性蛋白激酶激酶2（CAMKKK2）的小鼠是一种已知的中间激酶，该激酶已知可扩增巨噬细胞中的PAMP激活效应途径，显示NVR降低。中心假设是，通过激活CAMKK2介导的巨噬细胞效应子功能，PAMP刺激调节了NVR。具体而言，假设低级pAMP刺激以（1）增加血液中循环非细胞Ly6clo单核细胞的频率； （2）通过激活CAMKK2信号传导来促进LY6CLO单核细胞来源的巨噬细胞的激活，从而增加纤维生长因子的表达（图2）。纤维化因子募集并激活血管平滑肌细胞和肌纤维细胞，从而导致NVR的发展。 AIM 1将解决以下假设：在实验新血管形成中刺激的NVR是由非经典ly6clo血液单核细胞引起的活化巨噬细胞介导的。 AIM 2将解决CAMKK2调节巨噬细胞介导的NVR的假设。