Role of Tissue Resident Macrophages in Conventional Outflow Function

组织驻留巨噬细胞在常规流出功能中的作用

基本信息

批准号：
10544489
负责人：
Katy C Liu
金额：
$ 17.09万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10544489
关键词：
Ablation Adrenal Cortex Hormones Anterior Biological Assay Biological Response Modifiers Biomechanics Biometry Blindness Blood Blood Vessels Bone Marrow CD44 Antigens Cell physiology Cells Collagen Data Development Plans Distal Doctor of Philosophy Educational workshop Eligibility Determination Endothelium Environment Extracellular Matrix Eye Faculty Fellowship Flow Cytometry Foundations Funding Future Generations Genes Genetic Genetic Transcription Glaucoma Glucocorticoids Goals Grant Homeostasis Human Immune Immune response Immune system Immunologic Factors Immunology Immunomodulators Individual Institution Knowledge Label Lasers LoxP-flanked allele Macrophage Measures Mediating Mentors Mentorship Molecular Monitor Mus Nursing Faculty Ophthalmologist Pathway interactions Patients Phagocytes Phenotype Physiologic Intraocular Pressure Physiology Population Prostaglandins Publications Regulation Research Resistance Risk Factors Role Scientist Shapes Smooth Muscle Structure of sinus venosus of sclera Synthetic Prostaglandins Teacher Professional Development Testing Therapeutic Tissues Trabecular meshwork structure Training Transforming Growth Factor Beta 2 Transforming Growth Factor beta Vascularization Veins Work aqueous blind career career development confocal imaging design experience experimental study eye center improved lymphatic vessel meetings modifiable risk mouse genetics mouse model novel pharmacologic postnatal prenatal pressure programs repaired research faculty responsible research conduct single-cell RNA sequencing skills therapeutic target tool transcriptome treatment and outcome

项目摘要

PROJECT SUMMARY/ABSTRACT Candidate: The candidate, Katy Liu, is an MD/PhD glaucoma fellowship-trained, board-eligible ophthalmologist with a career goal of becoming an independent clinician-scientist. She has a PhD in Cell & Molecular Physiology, and her long-term objective is to better understand the pathobiology of the conventional outflow tract in order to improve treatments and outcomes in patients with glaucoma. Dr. Liu is completing a glaucoma research fellowship and will be promoted to faculty at the Duke Eye Center in July 2020. Career Development Plan: Dr. Liu proposes to investigate the role of tissue resident macrophages in conventional outflow homeostasis, which directly impacts the regulation of intraocular pressure (IOP). The proposed K08 will allow Dr. Liu to expand upon her current scientific knowledge and skills by gaining experience in ocular immunology, aqueous outflow physiology, genetic mouse models, flow cytometry and single-cell RNA sequencing. Dr. Liu will obtain formal didactics in ocular immunology, mouse genetics, biostatistics and responsible conduct of research. She will attend individual meetings with co-mentors to discuss career development, departmental seminars and faculty development workshops. Dr. Liu will regularly attend national meetings to discuss and present ongoing research, and submit her work for publication. Environment: The mentorship team consists of renowned experts in conventional outflow physiology and ocular immunology who are ideal to advise the candidate on her research. The Duke Eye Center is ideal for Dr. Liu with specific strengths in its Glaucoma research program and the Center for Ocular Immunology. She will also benefit from the world-class research and clinical faculty at the Duke Eye Center. Finally, the mentorship team and institution are fully committed to prepare Dr. Liu for independence as an R01-funded scientist. Research: Although immune regulators such as TGF-beta, corticosteroids and prostaglandin analogues are known to alter conventional outflow function, the role of the native immune system in conventional outflow homeostasis is poorly understood. This proposal is designed to test the hypothesis that tissue resident macrophages function in IOP regulation by altering extracellular matrix (ECM) homeostasis in the conventional outflow tract. In Aim 1, macrophages in the outflow tract will be characterized by lineage tracing and their functional effect measured by IOP and outflow facility following pharmacologic depletion or genetic deletion of macrophages. Aim 2 will assess changes to the ECM of the juxtacanalicular trabecular meshwork, the region of greatest outflow resistance generation in the conventional outflow tract, with macrophage deletion by measuring biomechanical stiffness and analyzing ECM components. Aim 2 will also reveal the TM macrophage-specific transcriptome which we will correlate with its functional role in the conventional outflow tract. This project will provide a better understanding of macrophage function in IOP homeostasis, which will influence future therapeutic strategies for glaucoma and serve as the foundation for a future R01 grant.

项目概要/摘要候选人：候选人 Katy Liu 是一位接受过青光眼奖学金培训的医学博士/博士，具有董事会资格眼科医生，其职业目标是成为一名独立的临床医生科学家。她拥有细胞和分子生理学，她的长期目标是更好地了解传统的病理学流出道，以改善青光眼患者的治疗和结果。刘博士正在完成一项青光眼研究奖学金，并将于 2020 年 7 月晋升为杜克眼科中心的教员。职业发展计划：刘博士建议研究组织驻留巨噬细胞在传统的流出稳态，直接影响眼压（IOP）的调节。这拟议的 K08 将使刘博士能够通过获得知识来扩展她当前的科学知识和技能在眼部免疫学、房水流出生理学、遗传小鼠模型、流式细胞术和单细胞 RNA 测序。刘博士将获得眼部免疫学、小鼠遗传学、生物统计学和负责任的研究行为。她将参加与共同导师的单独会议讨论职业发展、部门研讨会和教师发展研讨会。刘医生会定期参加全国会议讨论和展示正在进行的研究，并提交她的作品以供出版。环境：导师团队由传统流出生理学和眼部免疫学专家是为候选人的研究提供建议的理想人选。杜克眼科中心是医生的理想选择。刘在青光眼研究项目和眼部免疫学中心具有特殊优势。她会还受益于杜克眼科中心世界一流的研究和临床师资队伍。最后，指导团队和机构完全致力于帮助刘博士做好独立成为 R01 资助科学家的准备。研究：尽管 TGF-β、皮质类固醇和前列腺素类似物等免疫调节剂已知会改变常规流出功能，天然免疫系统在常规流出中的作用人们对体内平衡知之甚少。该提案旨在检验组织驻留的假设巨噬细胞通过改变传统细胞外基质（ECM）稳态来调节眼压流出道。在目标 1 中，流出道中的巨噬细胞将通过谱系追踪及其特征进行表征。药理学耗尽或基因缺失后通过 IOP 和流出设施测量的功能效应巨噬细胞。目标 2 将评估近小梁网 ECM 的变化，该区域在传统流出道中产生最大的流出阻力，通过删除巨噬细胞测量生物力学刚度并分析 ECM 组件。目标 2 还将揭示 TM 巨噬细胞特异性转录组，我们将其与其在常规流出中的功能作用相关联道。该项目将更好地了解巨噬细胞在眼压稳态中的功能，这将有助于影响青光眼未来的治疗策略，并作为未来 R01 资助的基础。