Longitudinal monitoring of microglial activation after stroke with SPION-enhanced MRI ABSTRACT: Microglia are the brain-resident macrophages that form the first line of immunological defense in the brain. Emerging evidence indicates that microglial activation and leukocyte infiltration play a major role in the pathogenic cascades of cerebral ischemia: cellular reactions determine the extent of ischemia-induced tissue damage but are also necessary for tissue repair and regeneration during recovery. Despite the existence of a number of prior experimental and clinical studies focusing on activated microglia for the study of neuroinflammation after focal cerebral ischemia, an accurate, efficacious, and non-invasive method for monitoring the functional alteration of microglia during stroke recovery is stil lacking. Our preliminary results suggest that microglial activity is involved in the restoration of the integrity of the blood-brain barrier (BBB) during neurovascular remodeling after stroke at all stages, ranging from the early pro-inflammatory (M1) to the later anti-inflammatory and tissue repair (M2) stages. We propose to test the hypothesis that the functional alteration of microglia shifts from a classical early pro-inflammatory activation to the later expression of growth factors involved in neurovascular remodeling. In this proposal we will focus on applying a novel technique for MRI detection of microglial-targeted, superparamagnetic nanoparticles in rat brain to evaluate the alteration of microglia functional activation during stroke recovery. In this projet, we propose the following two specific aims;
AIM1 to monitor the dynamic distribution profile of active microglia in rat ischemic brain with MRI and nanoparticles conjugated with a biomarker to microglia at 7, 14, and 28 days after stroke, and AIM2 to study the molecular and cellular changes during functional alterations of microglia in response to stroke-induced brain injury and recovery with histological and biochemical approaches. This proposal will combine the use of nanoparticles conjugated to an anti-Iba-1 antibody as a marker of microglia with MR imaging to non-invasively monitor the temporal profile of inflammation and microglia functional alteration in the brain after a stroke. Although the use of peripheral and imaging biomarkers have increased the specificity and sensitivity of the in vivo diagnosis of stroke, it would be of great clinical relevance to be able to non-invasively monitor the longitudinal development of inflammation in the brain of stroke subjects. MRI is widely used in medicine and widely available in clinical practice. Thus, an MRI method for imaging the inflammatory response inside the living stroked brain could be widely applied and would open these research areas to a great number of quantitative investigations in vivo where the efficacy of treatments could be determined and compared. This research will provide a novel experimental approach for monitoring the progression and treatment of stroke and other neurodegeneration disorders in support of direct subsequent applications in the clinic. In addition, the successful completion of the proposed studies will enhance our understanding of the functional alteration of microglia and the role of the key inflammatory events in neurovascular remodeling following stroke.
The proposed research is relevant to public health because evaluation of novel neurorestorative approaches will lead to the development of novel therapeutic strategies to significantly improve functional recovery of stroke. Experiments in this proposal are designed to focus on developing a novel technique combining nanoparticles with MRI in rat to evaluate alteration of microglial functional activation during stroke recovery. This proposal will provide a novel technical approach to experimental and clinical practices for monitoring the progression and treatment of stroke and other neurodegeneration disorders. Thus, this proposal is relevant to the part of NINDS's mission that pertains to developing significant knowledge in basic research that will create the foundation for treating ischemic stroke. This will help to reduce the burdens of this neurological disease.
| Yang, Yi; Kimura-Ohba, Shihoko; Thompson, Jeffrey F et al. (2018) Vascular tight junction disruption and angiogenesis in spontaneously hypertensive rat with neuroinflammatory white matter injury. Neurobiol Dis 114:95-110 |
| Yang, Yirong; Yang, Lisa Y; Orban, Lilla et al. (2018) Non-invasive vagus nerve stimulation reduces blood-brain barrier disruption in a rat model of ischemic stroke. Brain Stimul 11:689-698 |
