Wei Yang, PhD - US grants

This award is made in order to provide partial support for a workshop in plasticity and an associated commemorative book to honor Professor E.H. Lee on the occasion of his seventy-fifth birthday.

We request funds to establish a COBRE brain-lesioned patient database core facility. The brain-lesioned patient database will interface with local clinicians and organizations to identify/enroll individuals with brainlesions (e.g. stroke, resection) or other relevant conditions (e.g. autism). The brain-lesioned patient database core will expand to accommodate demand for different brain-lesioned patient groups. The establishment of the brain-lesioned patient database core will fill a major gap in cognitive neuroscience research needs at UNR. This core will directly support Projects 1 (Berryhill) and 2 (Caplovitz). Here, we are building infrastructure for use by researchers from the Psychology, particularly Clinical Psychology, and Biology Departments, and at the Medical School. The core will be located at UNR in Northern Nevada, an area with large Hispanic and Native American communities, and a large underserved rural population. The presence of a brain-lesioned patient database will make research in brain-lesioned populations possible by reducing the administrative and logistical challenges of assembling patient cohorts. Furthermore, the brain-lesioned patient database will be designed by the Nevada INBRE: Bioinformatics Core. The long-term goal will be to interface with other brain-lesioned database centers, such as UC Davis and to extend coverage throughout Nevada. The state of Nevada has a potentially large, untapped brain-lesioned patient population that is currently impossible for Nevada researchers to adequately study because this type of core resource does not exist. This will allow for the accumulation of rare and diverse patient populations to advance our understanding ofthe brain and facilitate research and treatment. The brain-lesioned patient database will be housed in Mack Social Science (MSS 411). This core will be directed by Jeffrey Hutsler (Assistant Professor, Department of Psychology, located in MSS 414). A database manager (TBN) will be hired from COBRE funding. Under Dr. Hutsler's supervision, the database manager will conduct neuropsychological screening tests and will schedule testing sessions.

Abstract Ischemic stroke is a devastating medical condition for which no pharmacologic intervention is available, except thrombolysis that can be used only for a small percentage of stroke patients. To improve stroke outcome, new pharmacologic approaches must be considered, such as boosting endogenous pro-survival pathways. Here, the unfolded protein response (UPR) is a promising target, because the UPR restores endoplasmic reticulum (ER) function, which is critical for survival of stressed cells. The ER plays a pivotal role in folding and processing newly synthesized proteins. ER function is impaired in a variety of stress conditions, including stroke, which results in accumulation of unfolded/misfolded proteins in the ER, a condition called ER stress. To resolve ER stress, the UPR activates adaptive responses that are mediated by 3 stress sensors in the ER membrane ? activating transcription factor-6 (ATF6), inositol-requiring enzyme-1 (IRE1), and protein kinase RNA-like ER kinase (PERK). These UPR branches have 3 primary functions: 1) increase protein-folding capacity, 2) decrease the ER load, and 3) eliminate accumulated unfolded/misfolded proteins from the ER. The UPR also modulates other pro-survival pathways including O-linked ?-N-acetylglucosamine (O-GlcNAc) modification. Although we know that stroke impairs ER function and activates the UPR, we do not yet know how the individual UPR branches define the fate and function of post-ischemic neurons in stroke, nor which UPR branch or branches play a predominant role in stroke outcome. Such knowledge is essential to developing a novel strategy to harness UPR pro-survival pathways for therapeutic benefits in stroke. Our long- term goal is to develop strategies to boost UPR pro-survival pathways for therapeutic purposes in stroke. The objective of this application is to establish the mechanistic link between the UPR and stroke outcome, and to identify the UPR branch or branches that critically define recovery of neurologic function after stroke. Our central hypothesis is that boosting pro-survival UPR and related pathways facilitates restoration of impaired ER function and cellular homeostasis in post-ischemic neurons, thereby improving stroke outcome. Based on our new unique UPR-selective and neuron-specific genetically modified mouse models, the hypothesis will be tested in the following specific aims: 1) Determine the role of ATF6 activation in stroke outcome; 2) Determine the contribution of the IRE1/XBP1/O-GlcNAc axis to stroke outcome; 3) Determine the role of the PERK branch in post-ischemic protein synthesis and stroke outcome. The proposed research is significant because we expect to uncover the mechanisms that link the UPR and downstream pathways to stroke outcome. Such knowledge will be a pivotal platform for future studies aimed at establishing new and innovative approaches to improve recovery of neurologic function after stroke, which critically defines quality of life for stroke patients.

Abstract Brain ischemia induced by cardiac arrest or stroke affects over one million people in the US every year, and can have devastating consequences. Ischemia-induced disability is major burden on families and healthcare systems. This problem will have an even greater impact as our population ages, because age is the key risk factor for cardiac arrest and ischemic stroke. Thus, there is an urgent need to define the role of age in outcome after brain ischemia/stroke in order to develop novel therapeutic strategies tailored for elderly ischemia/stroke patients. Ischemia is a severe form of metabolic stress that activates both pathological and protective path- ways. Outcome is improved when protective pathways dominate. The poor recovery of elderly patients after an ischemic event implies that aging is associated with a decline in the brain's capacity to activate pro-survival pathways after an ischemic episode. Indeed, activation of several pro-survival pathways is markedly impaired in aged brains. This is most evident in O-linked ?-N-acetylglucosamine (O-GlcNAc) modification of proteins, a post-translational modification and potent pro-survival pathway in a variety of stress conditions. While it is known that age is a key risk factor for poor outcome after brain ischemia/stroke and that activation of protective pathways improves outcome, we do not yet known how to apply this knowledge to improve outcome in aged patients who have suffered brain ischemia/stroke. Our long-term goal is to improve outcome in elderly patients after an ischemic event. The objective here is to determine why resistance to ischemic stress is decreased in aged brains, and to develop strategies to increase resistance. Our central hypothesis is that aging is associat- ed with a decline in the brain's capacity to activate protective pathways in response to stress conditions, and that boosting these pathways increases tolerance to stress. Based on results from ischemia experiments on aged animals, and using our new neuron-specific transgenic and knockout mouse models, we will test our hy- pothesis by pursuing the following specific aims: 1) Determine mechanisms underlying the age-related decline in the ability of the brain to activate O-GlcNAc modification upon transient forebrain ischemia and develop res- cue strategies; 2) Determine the extent to which boosting O-GlcNAc modification improves stroke outcome in aged brains. The proposed project is innovative because we will take a novel approach to neuroprotection that boosts an endogenous protective pathway, a substantial departure from current approaches that interfere with pathological pathways; we will focus on brain ischemia in aged animals; and importantly, this will the first study to investigate the O-GlcNAc pathway in brain ischemia/stroke. The proposed research is significant because we expect that this new approach to neuroprotection, specifically tailored to increase the resistance of aged brains to an ischemic challenge, will be a major breakthrough toward improving outcomes in elderly patients after an ischemic event.