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

• 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
• 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

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.

项目摘要/摘要 候选人：候选人凯蒂·刘是医学博士青光眼奖学金获得者，符合董事会资格 眼科医生，职业目标是成为一名独立的临床医生-科学家。她拥有细胞和细胞科学的博士学位。 分子生理学，她的长期目标是更好地了解传统的 流出道，以改善青光眼患者的治疗和预后。刘博士正在完成一项 他获得了青光眼研究奖学金，并将于2020年7月晋升为杜克眼科中心的教职员工。 职业发展规划：刘博士建议研究组织驻留巨噬细胞在 传统的流出动态平衡，直接影响眼压的调节。这个 建议的K08将允许刘博士通过获得 眼免疫学、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。刘博士将获得眼睛免疫学、小鼠遗传学、 生物统计学和负责任的研究行为。她将与共同导师一起参加个人会议，以 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 参加国家会议，讨论和介绍正在进行的研究，并提交她的工作以供出版。 环境：导师团队由传统流出生理学和 谁是理想的建议候选人的眼睛免疫学她的研究。杜克眼科中心是杜克医生的理想选择。 刘先生在青光眼研究项目和眼免疫中心拥有独特的优势。她会的 还受益于杜克眼科中心的世界级研究和临床教师。最后，导师制 团队和机构完全致力于为刘博士作为一名R01资助的科学家独立做好准备。 研究：尽管免疫调节剂如转化生长因子-β、皮质类固醇和前列腺素类似物 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 人们对动态平衡知之甚少。这项提议旨在检验组织驻留在 巨噬细胞通过改变细胞外基质(ECM)的稳态在眼压调节中的作用 流出道。在目标1中，流出道中的巨噬细胞将通过谱系追踪和它们的 药物耗竭或基因缺失后眼压和流出功能测定的功能效应 巨噬细胞。目标2将评估邻近小梁网的细胞外基质的变化，该区域 在传统的流出道中产生最大的流出阻力，巨噬细胞通过 测量生物力学刚度并分析ECM组件。Aim 2还将揭开TM的面纱 巨噬细胞特异性转录组，我们将与其在常规流出中的功能作用相关联 一条小路。这个项目将提供一个更好的理解巨噬细胞在眼压动态平衡中的作用，这将 影响未来青光眼的治疗策略，并作为未来R01拨款的基础。