Jianxiong Jiang, Ph.D. - US grants

DESCRIPTION (provided by applicant): My career goal is to be an independent and successful scientist dedicated to understanding the cellular and molecular mechanisms of brain injuries, and ultimately developing novel therapeutic strategies. As a postdoctoral fellow, I wanted to study neuroinflammation and neurodegeneration by focusing on a major neurological disorder such as epilepsy, which led me to pursue postdoctoral training in Dr. Dingledine's laboratory. Up to now my major research focus has been to understand how prostaglandin signaling regulates chronic brain inflammation and degeneration during and after seizures. We have pursued two major avenues of research 1) to develop small molecules that selectively modify prostaglandin receptor EP2, and 2) to determine how these compounds affect the pathologies in mouse models of epilepsy. We have made significant progress toward both goals and have developed novel selective allosteric potentiators and antagonists for EP2 receptor. More recently, we have found that pharmacological inhibition of EP2 receptors after pilocarpine-induced status epilepticus in mice provides many beneficial effects including reductions in mortality, weight loss, functional loss, neuroinflammation and neurodegeneration. We also demonstrated that EP2 receptors regulate expression of a variety of pro-inflammatory genes in microglia likely via cAMP/Epac signaling. The current K99/R00 research proposal focuses on extending these findings to provide a more complete understanding of prostaglandin signaling in the neuropathogenesis following seizures, by taking advantage of this newly identified group of antagonists together with two conditional knockout mouse strains in which EP2 receptors are ablated either in forebrain neurons or microglia/macrophages. Successful completion of these studies will provide new insights on the regulation of inflammation and injury in epileptic brain that should be relevant to many other acute and chronic neurodegenerative disorders involving neuroinflammation with EP2 activation, including stroke, multiple sclerosis and Alzheimer's disease. Thus, this research could provide guidance to develop novel therapies for the treatment of those diseases. The research environment at Emory University is quite friendly, accommodating and collaborative. My expertise and experiences have prepared me to lead the proposed project, and my mentors (Dr. Raymond Dingledine and Dr. James McNamara) will provide mentoring, training, and oversight in epilepsy models, neuropathology, behavioral neuroscience, and guidance in project administration (e.g. staffing, regulatory issues and budget). I will also receive training from Dr. Kerry Ressler for lentiviral-mediated RNA interference in the mouse hippocampus, take courses on advanced neuroscience techniques, research ethics and lab management, and participate in scientific meetings. Overall, my proposal is very relevant to the goals of the NIH Pathway to Independence Award by providing technical and administrative training, establishing my own research projects, allowing me to pursue funding from the NIH, and ultimately facilitating my transition to an independent investigator.

PROJECT SUMMARY Epilepsy is a common neurological disorder that afflicts about 1% of the population. Although seizures can be partially controlled by current medications, there is no US FDA-approved drug that can provide disease prevention or modification despite remarkable advances in epilepsy treatment over the past decades. A major obstacle to finding such an antiepileptogenic drug is that the molecular mechanisms by which a normal brain is transformed to generate epileptic seizures remain unsolved. Accumulating evidence from recent clinical and preclinical studies suggests that the abnormal activation of the brain-derived neurotrophic factor (BDNF) receptor TrkB (tropomyosin-related kinase receptor B) and its downstream effector phospholipase C?1 (PLC?1) is sufficient to produce epilepsy following status epilepticus (SE). As TrkB and PLC?1 are emerging as attractive molecular targets to prevent acquired epilepsy, a key unsolved puzzle is the signaling events that are triggered by SE and cause the irregular BDNF/TrkA activity in the hippocampus, thereby leading to epileptogenesis. In preliminary studies we have demonstrated that the seizure-induced hippocampal BDNF/TrkB abnormality is largely suppressed by blocking prostaglandin E2 (PGE2) synthesis or signaling. Our main hypothesis is that PGE2 via a G?s-dependent signaling pathway upregulates hippocampal BDNF/TrkB activity and contributes to epileptogenesis following prolonged seizures. Our general approach is to use biochemical, pharmacological, genetic tools, and multiple in vitro and in vivo model systems to test a hypothesis that PGE2 is involved in the hippocampal BDNF induction and TrkB activation after SE, to determine whether seizure-mediated BDNF/TrkB activity involves cAMP/PKA signaling and which G?s-coupled PGE2 receptor is engaged, and to determine whether PGE2 signaling via its G?s-coupled receptors plays a dominant role in the development of epilepsy and/or the associated behavioral comorbidities after SE. Successful completion of this project might lead to the discovery of novel molecular targets for the prevention strategies of acquired epilepsy.

PROJECT SUMMARY Gliomas, the most common type of primary brain tumors, constitute a significant cause of epilepsy, particularly among the elderly. Current standard treatment, surgical resection followed by radiotherapy and chemotherapy with temozolomide, merely provides a limited increase of median survival. As the leading presenting symptom of malignant brain tumors, seizures often recur and aggravate during the course of illness. Despite the high frequency of incidence, seizures caused by gliomas are poorly managed, as nearly 50% of patients show resistance to current antiepileptic drugs (AEDs) and status epilepticus (SE) has been reported in more than 10% of all malignant glioma cases. Refractory epilepsy represents a major impediment to tumor management; therefore, there is a dire need for new therapies with sufficient efficacy for glioma patients who also suffer from uncontrollable seizures. However, the molecular mechanisms of epileptogenesis in malignant tumor-bearing brains are poorly understood. Recent evidence suggests that cyclooxygenase-2 (COX-2), a likely contributor to some forms of acquired epilepsy, might be involved in the development of malignant gliomas via producing prostaglandin E2 (PGE2). We show that PGE2 facilitates tumor cell proliferation, invasion and inflammation largely through the G?s-coupled EP2 receptor, and that activation of EP2 aggravates neuronal inflammation and degeneration after prolonged seizures in epileptic rodents. Our main hypothesis is that blocking the inflammatory prostaglandin receptor EP2 will impair the development of gliomas and thus suppress the concomitant seizures. To test this hypothesis, we will use a combination of pharmacological and genetic approaches to delineate the PGE2/EP2 signaling-mediated inflammation in human malignant glioma cells (Aim 1), and to determine the effects of EP2 receptor inhibition on the development of spontaneous seizures associated with malignant gliomas (Aim 2). Successful completion of this project will lead to the identification of novel molecular targets for the prevention and/or modification strategy for malignant gliomas and the concomitant epilepsy.