University of Texas Specialized Program in Acute Stroke

在此次SPOTRIAS申请中，我们提出了3项新研究，其中一项（项目#1）是在多个SPOTRIAS中心进行的合作多中心II期试验，一项全新的项目（项目#2），另一项（项目#3）是在我们SPOTRIAS项目的前5年开始的项目的下一阶段。这三个项目都是真正意义上的翻译。项目1是一项神经保护治疗（咖啡醇和低温）组合的试验，其中一种（咖啡醇）是在我们的实验室中发现的，并在我们的动物中风模型中进行了广泛的临床前测试。该组合也首次在我们的实验室进行了测试。这些治疗的I期和早期II期评价是UT和UC San Diego的第一个SPOTRIAS的一部分，并显示了可行性和安全性。本着翻译的精神，我们在项目1中共同提出的研究旨在尽可能多地复制实验室实验，这些实验证明了这种组合的最强大益处。本研究的目的是进行一项析因设计II期研究，比较两种治疗单独和联合治疗与标准治疗，以尽快确定哪些治疗组应进入III期研究。项目2是一项在ICH患者中进行的PPARgamma激动剂研究。我们的实验室是第一个在ICH动物模型中证明PPARgamma表达变化的实验室，项目2的PI是第一个发现PPARgamma激动剂促进包含血肿的红细胞吞噬作用的实验室团队的一部分。 项目2是该工作的直接临床翻译。最后，项目3继续我们以前的工作与超声增强血块溶解。超声的安全性和益处已经在我们的动物中风模型和其他实验室中进行了测试，然后在我们之前的SPOTRIAS的2期研究中进行了测试。为了使这种治疗更广泛地应用，我们开发了一种免提超声装置，我们首先在动物身上进行了测试，作为我们第一个SPOTRIAS的补充奖励的一部分，现在我们计划首次在人类身上进行测试。我们还提出了3个核心（临床，数据和组织）来支持这些转化研究，以及一个职业发展计划来培训新的研究人员进行未来的转化研究。所有这些项目和核心都通过了我们先前的赠款审查，但我们在这次重新提交中彻底解决了对数据核心和项目#1的担忧。

In this SPOTRIAS application, we propose 3 new studies, one of which (project #1) is a collaborative multicenter phase 2 trial across several SPOTRIAS centers, one entirely new project (project # 2), and one (project #3) which is the next phase of a project started during the first 5 years of our SPOTRIAS program. All three of these projects are translational in the true sense of the word. Project 1 is a trial of a combination of neuroprotective treatments (caffeinol and hypothermia), one of which (caffeinol) was discovered in our lab and has undergone extensive preclinical testing in our animal stroke models. The combination was also first tested in our lab. The phase 1 and early phase 2 evaluations of these treatments were part of the first SPOTRIAS from UT and UC San Diego, and showed feasibility and safety. In the spirit of translation, the study that we jointly propose in Project 1 is designed to replicate as much as possible the laboratory experiments which demonstrated the most robust benefit of this combination. The purpose of this study is to do a factorial design phase 2 study of both treatments alone and in combination compared with standard treatment in order to determine as quickly as possible which treatment arms should move forward to a phase 3 study. Project 2 is a study of a PPARgamma agonist in patients with ICH. Our lab was the first to demonstrate changes in PPARgamma expression in an animal model of ICH, and the PI of Project 2 was part of the lab team that first discovered that PPAR gamma agonists promoted the phagocytosis of the red blood cells comprising the hematoma. Project 2 is a direct clinical translation of that work. Finally, project 3 carries on our previous work with ultrasound enhanced clot lysis. The safety and benefit of ultrasound has been tested in our animal stroke models and in other labs, and then in a phase 2 study as part of our previous SPOTRIAS. In an effort to make this treatment more widely applicable, we have developed a hands-free ultrasound unit that we first tested in animals as part of a supplementary award to our first SPOTRIAS, and now propose to test for the first time in humans. We also propose 3 Cores (Clinical, Data, and Tissue) to support these translational studies, and a Career Development Program to train new investigators to carry out future translational studies. All of these projects and Cores were approved by the previous review of our grant, but there were concerns about the Data Core and Project #1 that we have thoroughly addressed in this re-submission.