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）：过去十年中的心血管研究明确表明，激素醛固酮具有炎症性血管作用，包括内皮细胞的生物物理变化，例如：增加细胞刚度，增加细胞体积，增加的细胞体积，增加的表面粘附分子表达和减少一氮氧化物的产生。然而，尚未研究的是，这些醛固酮诱导的内皮细胞机械性能的改变会影响镰状细胞的血管酸性，这也是一种生物物理现象，醛固酮也可能改变了血细胞的生物物理特性。我们假设醛固酮介导的细胞机械作用会影响镰状细胞的血管牙合，并建议使用我们以前与常规测定法相结合开发的单细胞机械技术，以探索醛固酮如何影响微血管闭塞。具体而言，我们将确定并研究醛固酮对镰状红细胞和白细胞内皮粘附的影响的潜在机制（AIM 1），镰状红细胞和白细胞变形性（AIM 2），以及三维微型模型的微腔模型（AIM 2）。该候选人选择了一种新颖的培训和职业道路，最近完成了小儿血液学/肿瘤学研究金，并在生物工程领域结合了博士学位。这项K08赠款将使Lam博士能够接受所有必要的培训，以发展为新的学术医学领域的独立研究人员：一名医生 - 科学家工程师，他们应用生物工程和纳米科学技术来开发新的生物医学设备，以诊断和研究儿科血液疾病。具体而言，该奖项将用于进一步培训他在血管生物学，粘附的细胞生物学以及先进的微型制作和微流体学以开发用于镰状细胞疾病的复杂实验室芯片设备。这项研究将在加州大学伯克利分校的独特生物工程实验室中进行，该实验室的重点是应用和开发新的光学显微镜，力显微镜和微流体技术来研究健康和疾病的细胞力学，并在UC San Francisco的临床连接密切的临床联系。相关性（请参阅说明）：通过研究激素醛固酮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疾病的新疗法的理解。此外，我们为该项目开发的设备将作为新的诊断和药物发现工具的原型，用于这种衰弱的和潜在的致命疾病，每天都会影响成千上万的美国人的生活。