A Putative Heparin Receptor in Smooth Muscle Cells

描述（由申请人提供）：在西方国家，心血管疾病是导致死亡人数最多的疾病。此外，在2010年的医疗保健支出中，血管疾病患者的治疗预计将超过3000亿美元。有证据表明，药物肝素可以有效地短期治疗心血管疾病的许多症状，实验室研究表明，肝素可以减缓血管平滑肌细胞的生长，这是晚期血管疾病的一个组成部分。PI实验室的长期研究目标是了解肝素治疗如何导致血管细胞功能的变化。这些知识可能有助于开发血管疾病的先进治疗方法。此前，PI的实验室开发了一种抗体，可以模拟肝素对培养血管细胞的影响，这些抗体已用于研究血管平滑肌细胞增殖是如何被抑制的证据。这项研究的目的是通过首先评估对肝素的整体反应，而不仅仅是那些事先预测的特定变化，来增强对肝素的理解。这将涉及使用阵列技术，该技术可以同时检测许多不同基因的变化。将进一步评估使用该技术确定的具体目标。其次，肝素受体的蛋白质和基因将使用用于蛋白质鉴定和序列测定的质谱技术进行鉴定。来自已鉴定蛋白质的序列信息将用于创建新的工具，这些工具将用于进一步确认肝素受体的鉴定。第三，基于我们实验室之前的工作，确定了肝素受体可能的信号系统，我们建议比较通过肝素受体和触发类似细胞内通路的受体的信号传导结果，以增加我们对肝素信号传导的理解。第四，心血管疾病具有显著的炎症成分，可能也是肝素作用的靶点，这与我们的初步结果一致。肝素治疗减少血管平滑肌细胞炎症反应的能力将被评估。此外，炎症介质诱导的特定基因表达的变化，包括一系列显著改变的基因类型，将在培养的内皮细胞中进行肝素治疗和不同时进行肝素治疗。如果肝素治疗导致基因表达的炎症变化减少，数据将支持肝素信号传导与血管中炎症信号传导相反的假设。结合本工作的其他结果，这些数据将为肝素改变血管细胞行为的机制提供坚实的理解，并为肝素受体可能成为血管疾病高级治疗靶点的途径提供建议。

DESCRIPTION (provided by applicant): Cardiovascular diseases account for more deaths than any other disease in western countries. In addition, treatment of individuals with vascular diseases is expected to account for more than $300 billion in health care spending in 2010. Evidence suggests that the drug heparin can be an effective short-term treatment for many of the symptoms of cardiovascular disease, and laboratory studies indicate that heparin slows vascular smooth muscle cell growth, a component of late stage vascular disease. The long-term research goals in the PI's laboratory are to understand how heparin treatment results in changes in vascular cell function. Such knowledge is likely to contribute to the development of advanced treatments for vascular diseases. Previously, the PI's laboratory developed antibodies that mimic heparin effects on vascular cells in culture and those antibodies have been used in studies that resulted in evidence for how vascular smooth muscle cell proliferation is inhibited. The research aims for the current proposal will enhance that understanding by first evaluating the entire response to heparin rather than only those specific changes that were predicted in advance. This will involve using array technology that can examine changes in many different genes at one time. Specific targets identified using this technology will be evaluated further. Second, the protein and gene for the heparin receptor will be identified using mass spectrometry techniques developed for protein identification and sequence determination. Sequence information from the identified protein will be used to create new tools that will be used to further confirm the identification of the heparin receptor. Third, based on previous work from our laboratory that identified a likely signal system from the heparin receptor, we propose to compare the results of signaling through the heparin receptor and receptors that trigger similar intracellular pathways to increase our understanding of heparin signaling. Fourth, cardiovascular disease has a significant inflammatory component that is likely to also be a target of heparin action, consistent with our preliminary results. The ability of heparin treatment to decrease inflammatory responses in vascular smooth muscle cells will be evaluated. In addition, changes in expression of specific genes induced by inflammatory mediators that cover a range of significantly altered gene types will be examined in cultured endothelial cells with and without concurrent heparin treatment. If heparin treatment results in decreased inflammatory changes in gene expression, the data will support the hypothesis that heparin signaling acts counter to inflammatory signaling in the vasculature. Coupled with the other results of this work, these data will provide a solid understanding of the mechanisms by which heparin alters vascular cell behavior and suggestions for ways in which the heparin receptor could be a target for advanced therapies for vascular diseases. PUBLIC HEALTH RELEVANCE: Deaths from cardiovascular disease and spending on treatments for individuals suffering from these diseases are major factors in the costs of health care. The drug heparin has been suggested as a treatment that could decrease progression of the disease, but we have a limited understanding of how heparin might work to help slow disease progress. The proposed research is designed to increase our understanding of how the drug heparin works at the molecular level to decrease inflammation in blood vessels, and should therefore facilitate development of new treatment strategies for vascular disease.