Microfluidic assays for hyper-reactive platelets in diabetes

糖尿病高反应性血小板的微流控检测

• 批准号: 9199213
• 负责人: Hang Lu
• 金额: $ 22.8万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199213
• 关键词: Adhesions; Adopted; Affinity; Agonist; Automation; Behavior; Binding; Biochemical; Biochemical Process; Biological Assay; Biology; Biomechanics; Blood; Blood Platelet Disorders; Blood Platelets; Blood specimen; Cardiovascular Diseases; Cell Adhesion; Cigarette Smoker; Clinical; Collaborations; Complex; Coupled; Data; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Disease Progression; Drops; Engineering; Event; Future; Goals; Hyperactive behavior; Hypertension; Integrins; Kinetics; Knowledge; Lead; Literature; Microfluidics; Modification; Molecular; Molecular Conformation; Molecular Probes; Morphology; Obesity; P-Selectin; Pathologic; Patients; Pattern; Physicians; Platelet Activation; Platelet Count measurement; Play; Process; Regulation; Reporter; Resolution; Risk Factors; Role; Shapes; Surface; System; Technology; Testing; Thrombosis; Time; Up-Regulation; Validation; Work; atherothrombosis; base; clinical Diagnosis; clinical application; design; diabetic; diabetic patient; experience; experimental study; high throughput screening; image processing; innovation; insight; public health relevance; receptor; tool; von Willebrand Factor

 DESCRIPTION (provided by applicant): Diabetes, obesity, and hypertension among other cardiovascular diseases are large risk factors for platelet hyperreactivity. Despite the importance, the molecular mechanisms of the platelet hyperreactivity are still unknown. Our long-term goal is to integrate biomechanical and biochemical approaches to understand the disease mechanisms in patients with diabetes, obesity and cardiovascular diseases, and to use this knowledge to design tools that facilitate physicians' decisions on treatment of these diseases - tools to diagnose, tools to follow disease progression, and tools to follow treatment courses. Using a unique single-platelet Biomembrane Force Probe (BFP) assay, we have gathered preliminary evidence that there exists an intermediate state of platelets (discoid in shape but express low-level markers of activation) and this state is primarily characterized by having integrin molecules adopting a conformation that gives rise to intermediate affinity. We hypothesize that this intermediate state plays an important role in platelet hyperactivity in diabetics. While this assay is sensitive and powerful for probing molecular interactions on single platelets, it is very labor-intensive and low throughput. The goal of this project is to design a simple-to-use and yet high-throughput and highly informative microfluidic approach to understand sequences of molecular events that lead to platelet activation. We will obtain detailed characterization of the intermediate state, its stability, and the kinetics of state changs of the normal and diseased platelets using this approach. Validation of the new assay and proof of the hyperactivity hypothesis will allow this assay to be further developed in the future for clinical diagnosis or to follow treatment of atherothrombosis in patients. We have assembled a team of engineers and clinicians for this project. The work is innovative because no such high-throughput assay that yields mechanistic insights (and only using a drop of blood) is currently available, and that understanding the role of the intermediate state of platelets, particularly in diabetes, will lead to a significant improvement in diagnostic and treatment for platelet hyperactivity disorders.

 描述（由适用提供）：其他心血管疾病的糖尿病，肥胖和高血压是血小板过度反应性的大风险因素。尽管很重要，但血小板过度反应性的分子机制仍然未知。我们的长期目标是整合生物力学和生化方法，以了解糖尿病，肥胖症和心血管疾病患者的疾病机制，并使用这些知识来设计工具，以促进医生在治疗这些疾病方面的决定 - 诊断疾病进展的工具，以遵循疾病进展，以遵循治疗疗法，以进行治疗。使用独特的单位物质生物膜力探针（BFP）测定法，我们收集了初步的证据，表明存在一个中间状态血小板状态（形状盘状，但表达低级激活标记），并且该状态的主要特征是具有整合素分子的构素的特征，这些构素可产生与中间的亲属相结合。我们假设该中间状态在糖尿病患者的血小板多动症中起重要作用。虽然该测定法对单个血小板上的分子相互作用敏感且有力，但它是非常密集且吞吐量低的。该项目的目的是设计一种简单且高通量和高度信息的微流体方法，以了解导致血小板激活的分子事件序列。我们将使用这种方法来获得中间状态，其稳定性和状态变化的动力学的详细表征。对新测定的验证和多动症假说的证明将使将来进一步开发用于临床诊断或遵循患者动脉粥样硬化的治疗。我们已经为这个项目组成了一个工程师和临床医生团队。这项工作具有创新性，因为目前没有这样的高通量测定能够产生机械洞察力（并且仅使用一滴血液），并且了解血小板中间状态的作用，尤其是在糖尿病中，将导致血小板多活性疾病的诊断和治疗可显着改善。