Therapeutic targeting of CD36 after intracerebral hemorrhage

描述(申请人提供)：脑出血(ICH)是出血性中风最常见的形式，占所有中风的15%，每年有37,000-52,400名美国人患有脑出血。在所有类型的中风中，ICH具有最高的急性死亡率和最差的长期神经后果。ICH是由大脑内血管破裂引起的，导致形成占位的血肿。临床上，血肿量与神经功能恶化和较高的死亡率有关；然而，许多脑出血患者不适合进行手术，和/或存在病变大小/位置不佳的情况，限制了神经外科干预的有效性。此外，缺乏促进血肿清除的有效医疗选择，这对临床实践构成了一个关键障碍。我们的长期目标是确定分子和细胞途径 有助于脑出血后血栓的溶解。这些知识将为药物开发提供一个框架，以改善脑出血后患者的预后。我们的试验数据表明，咖喱香料，姜黄素，促进脑出血后血肿的消退，因此可能是一种新的安全的治疗选择。具体目标1将验证CD36介导姜黄素诱导的脑出血后血肿清除的假设。特异性目标2将验证C/EBP-1介导姜黄素诱导的CD36表达和脑出血后血肿消退的假设。总之，拟议的研究将阐明姜黄素促进血肿消退的分子和细胞机制。这些研究的结果将为针对C/EBP-1和/或CD36的药物开发提供一个框架，以改善脑出血后的临床结果。

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, accounts for up to 15% of all strokes, with 37,000-52,400 Americans suffering an ICH annually. ICH has the highest acute mortality and the worst long-term neurological outcomes of all types of stroke. ICH is caused by a ruptured blood vessel within the brain, leading to the formation of a space occupying hematoma. Hematoma volume is clinically associated with neurological deterioration and higher mortality; however, many ICH patients are poor surgical candidates and/or present with an unfavorable size/location of the lesion, restricting the utility of neurosurgical intervention. Furthermore, efficacious medical treatment options to promote hematoma clearance are lacking, presenting a critical barrier to clinical practice. Our long-term objective is to identify the molecular and cellular pathways which contribute to clot resolution after ICH. This knowledge will provide a framework for pharmaceutical development to improve patient outcomes after ICH. Our pilot data suggest the curry spice, curcumin, promotes hematoma resolution after ICH and may therefore represent a novel and safe treatment option. Specific Aim 1 will test the hypothesis that CD36 mediates curcumin-induced hematoma clearance after ICH. Specific Aim 2 will test the hypothesis that C/EBP-¿ mediates curcumin-induced CD36 expression and hematoma resolution after ICH. Together, the proposed studies will elucidate the molecular and cellular mechanisms which underlie the ability of curcumin to promote hematoma resolution. The results of these studies will provide a framework for pharmaceutical development targeting C/EBP-¿ and/or CD36 to improve clinical outcomes after ICH.