Nanomechanical effects of aldosterone on vaso-occulation in sickle cell disease

醛固酮对镰状细胞病血管阻塞的纳米力学影响

• 批准号: 8014934
• 负责人: Wilbur A Lam
• 金额: $ 13.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-08 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8014934
• 关键词: Acute leukemia; Adhesions; Adhesiveness; Affect; Aldosterone; American; Anatomy; Area; Atomic Force Microscopy; Attenuated; Award; Biological Assay; Biology; Biomedical Engineering; Biophysical Process; Blocking Antibodies; Blood; Blood Cells; Blood Vessels; Blood flow; Breeding; Cardiovascular system; Categories; Cell Adhesion; Cell Adhesion Molecules; Cell Aggregation; Cell Volumes; Cell-Cell Adhesion; Cells; Cellular biology; Childhood; Clinical; Complex; Coupled; Dependence; Devices; Diagnosis; Disease; Doctor of Philosophy; Dose; Endothelial Cells; Engineering; Erythrocytes; Fellowship; Fluorescence Microscopy; Functional disorder; Grant; Health; Hematological Disease; Hormones; In Vitro; Inflammation Mediators; Inflammatory; Instruction; Lead; Leukocytes; Life; Literature; Measurement; Measures; Mechanics; Mediating; Medicine; Microcirculation; Microfabrication; Microfluidics; Microscopy; Modeling; Molecular; Mononuclear; Nanotechnology; Nitric Oxide; Optics; Paper; Pathologic; Patients; Pediatric Hematology/Oncology; Pharmaceutical Preparations; Physicians; Play; Population; Principal Investigator; Process; Production; Property; Publishing; Relative (related person); Reporting; Research; Research Personnel; Reticulocytes; Risk; Role; Sampling; San Francisco; Scientist; Shapes; Sickle Cell; Sickle Cell Anemia; Spironolactone; Surface; System; Techniques; Testing; Therapeutic; Time; Training; Work; career; drug discovery; eplerenone; granulocyte; improved; in vitro Model; monolayer; nanomechanical; nanoscale; nanoscience; novel; novel diagnostics; prototype; research study; sickling; therapeutic target; tool

DESCRIPTION (provided by applicant): Cardiovascular research in the last decade has definitively shown that the hormone aldosterone has pro- inflammatory vascular effects, including biophysical changes in endothelial cells such as: increased cell stiffness, increased cell volume, increased surface adhesion molecule expression, and decreased nitric oxide production, among others. What has not been studied, however, is how these aldosterone-induced alterations in endothelial cell mechanical properties affect sickle cell vaso-occlusion, which is also a biophysical phenomenon, and how aldosterone may also alter the biophysical properties of blood cells. We hypothesize that aldosterone-mediated cell mechanical effects influence sickle cell vaso-occlusion and propose to use single-cell mechanical techniques that we have previously developed in combination with conventional assays to explore how aldosterone affects microvascular occlusion. Specifically, we will determine and investigate the underlying mechanisms of aldosterone's effect on endothelial adhesion to sickle red cells and leukocytes (Aim 1), sickle red cell and leukocyte deformability (Aim 2), and cell aggregation and microcirculatory flow in a three-dimensional in vitro model of the microvasculature (Aim 3). The candidate has chosen a novel training and career path and has recently completed a fellowship in pediatric hematology/oncology combined with a PhD in bioengineering. This K08 grant will allow Dr. Lam to receive all the necessary training to develop into a new breed of independent researcher in academic medicine: a physician-scientist-engineer who applies bioengineering and nanoscience techniques to develop new biomedical devices for diagnosis and study of pediatric blood diseases. Specifically, this award will be used to further his training in vascular biology, the cell biology of adhesion, and advanced microfabrication and microfluidics to develop complex lab-on-chip devices for sickle cell disease. This research will be conducted in a unique bioengineering lab at UC Berkeley that focuses on applying and developing new optical microscopy, force microscopy, and microfluidic techniques to study cell mechanics in health and disease, with close clinical connections at UC San Francisco. RELEVANCE (See instructions): By investigating whether the hormone aldosterone plays a role in sickle cell anemia, this work will improve our understanding of- and new treatments for-this complex and incurable disease. In addition, the devices we develop for this project will serve as prototypes for new diagnostic and drug discovery tools for this debilitating and potentially fatal disease that affects the lives of tens of thousands of Americans every day.

描述（由申请人提供）：在过去十年中的心血管研究已经明确显示激素醛固酮具有促炎性血管作用，包括内皮细胞中的生物物理变化，例如：增加的细胞硬度、增加的细胞体积、增加的表面粘附分子表达和减少的一氧化氮产生等.然而，尚未研究的是这些醛固酮诱导的内皮细胞机械性质的改变如何影响镰状细胞血管闭塞，这也是一种生物物理现象，以及醛固酮如何也可能改变血细胞的生物物理性质。我们假设醛固酮介导的细胞机械效应影响镰状细胞血管闭塞，并建议使用单细胞机械技术，我们以前开发的结合传统的检测方法，探讨醛固酮如何影响微血管闭塞。具体而言，我们将确定和研究醛固酮对内皮细胞粘附镰状红细胞和白细胞（目标1），镰状红细胞和白细胞变形性（目标2），细胞聚集和微循环流动的三维体外模型的微血管系统（目标3）的影响的潜在机制。候选人选择了一条新的培训和职业道路，最近完成了儿科血液学/肿瘤学奖学金，并获得了生物工程博士学位。这K 08赠款将允许林博士接受所有必要的培训，发展成为一个新的品种的独立研究人员在学术医学：一个医生，科学家，工程师谁应用生物工程和纳米科学技术，开发新的生物医学设备的诊断和儿科血液疾病的研究。具体而言，该奖项将用于进一步培训他在血管生物学，细胞生物学的粘附，先进的微加工和微流体开发复杂的芯片实验室设备的镰状细胞病。这项研究将在加州大学伯克利分校一个独特的生物工程实验室进行，该实验室专注于应用和开发新的光学显微镜，力显微镜和微流体技术，以研究健康和疾病中的细胞力学，并与加州大学旧金山分校弗朗西斯科密切临床联系。相关性（参见说明）：通过研究醛固酮激素是否在镰状细胞性贫血中起作用，这项工作将提高我们对这种复杂且无法治愈的疾病的理解和新的治疗方法。此外，我们为这个项目开发的设备将作为新的诊断和药物发现工具的原型，用于这种每天影响成千上万美国人生活的使人衰弱和潜在致命的疾病。