Approximately 795,000 people have a stroke in the U.S. every year, and about 6.3 million people died from stroke worldwide in 2015. There are many different pathophysiological processes that can result in stroke, and thus, stroke does not demonstrate a single pathology. The two main classifications of stroke are acute ischemic stroke (AIS), caused by a blockage of blood flow to the brain, and hemorrhagic stroke, the most common type of which is intracerebral hemorrhage (ICH), caused by bleeding into the brain. The extensive pathophysiological response during a stroke is complex and involves multiple mechanisms, including throm- bosis, inflammatory and excitotoxicity responses, and apoptosis, all of which contribute to neuronal injury, cell death, and the breakdown of the blood brain barrier (BBB). High-density lipoproteins (HDL) play a critical role in the prevention of CVD and have been found to form distinct stable subspecies, each with their own unique complement of proteins and lipids, some of which are implicated in disease processes associated with di- verse types of diseases. Several clinical studies have shown an inverse relationship between HDL-C (choles- terol) and stroke risk. Our previous research discovered that the HDL-associated proteins apolipoprotein A-I and paraoxonase-1 were less abundant in AIS compared with healthy subjects. To further explore these find- ings, the objective of this application is to identify HDL subspecies that are related to stroke and to eluci- date their mechanistic connection with stroke. We hypothesize that by analyzing the HDL proteome in stroke patients compared with non-stroke subjects, we can identify specific HDL subspecies that are involved in stroke pathophysiology, specifically those subspecies that are likely to affect stroke pathogenesis through one of HDL's many known functions, in particular, its anti-thrombotic properties. We will pursue the following spe- cific aims: (1) Proteomic profiling of HDL subfractions from stroke and non-stroke subjects (Years 1-3). (2) Computational identification and prioritization of stroke-related HDL subspecies in plasma (Years 2-4). (3) Experimental validation and mechanistic evaluation of stroke-related HDL subspecies (Years 3-5). This proposal is a renewal of the PI's first R01 grant (R01-HL111829, 08/01/2012-06/30/2018). It is a nat- ural extension of our prolific research on HDL subspecies and their role in healthy subjects to now focus on stroke. The proposal builds on the solid clinical evidence linking HDL and stroke, yet is highly innovative in that it will be among the first to definitively associate HDL subspeciation with stroke. As such, it will fill a major gap in our understanding of the compositional and functional heterogeneity of HDL particles and defining their association with stroke. Our research will have a significant impact because it will facilitate our molecular understanding of HDL functions by revealing the mechanisms by which HDL subspecies affect stroke pathol- ogy. Further investigation of these HDL subspecies in the long-term has the potential to substantially improve the current diagnostic and treatment paradigm for stroke and optimize outcomes for this devastating disease.

Public Health Relevance

In the U.S., stroke is the country's fifth leading cause of mortality. Recent clinical studies have established con- vincing link between HDL and stroke risk. The objective of this application is to identify HDL proteins and/or subspecies that are related to stroke, and to elucidate their mechanistic connection with stroke. The study will facilitate our molecular understanding of HDL functions and has the potential to substantially improve the cur- rent diagnostic and treatment paradigm for stroke and optimize outcomes for this devastating disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Modeling and Analysis of Biological Systems Study Section (MABS)
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Liu, Lijuan
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Cincinnati Children's Hospital Medical Center
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