Prostaglandin signaling following seizures
Principal Investigator: Jianxiong Jiang
Abstract: 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.
Funding Period: 2013-04-01 - 2015-03-31
more information: NIH RePORT
- Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotectionJianxiong Jiang
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA
Trends Pharmacol Sci 34:413-23. 2013..Understanding the conditions under which multiple EP2 signaling pathways are engaged might suggest novel therapeutic strategies to target this key inflammatory prostaglandin receptor. ..
- Cyclooxygenase-2 in epilepsyAsheebo Rojas
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, U S A
Epilepsia 55:17-25. 2014....
- Lead optimization studies of cinnamic amide EP2 antagonistsThota Ganesh
Department of Pharmacology, School of Medicine, Emory University, 1510 Clifton Road, Atlanta, Georgia 30322, United States
J Med Chem 57:4173-84. 2014..Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role. ..
- Development of second generation EP2 antagonists with high selectivityThota Ganesh
Department of Pharmacology, School of Medicine, Emory University, 1510 Clifton Rd, Atlanta, GA 30322, USA Electronic address
Eur J Med Chem 82:521-35. 2014..Thus, we now developed a second generation compounds that devoid of the acrylamide functionality and possess high potency and improved (>1000-fold) selectivity to EP2 over other prostanoid receptors. ..
- MOLECULAR AND CELLULAR MECHANISMS OF OSTEOPOROSISStavros C Manolagas; Fiscal Year: 2013....
- CNS injury caused by HIV-1 and alcohol: Protective effects of CB2 activationYuri Persidsky; Fiscal Year: 2013..abstract_text> ..
- Emory Alzheimer's Disease CenterAllan I Levey; Fiscal Year: 2013..abstract_text> ..
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- Expanding the National Health AccountsDavid M Cutler; Fiscal Year: 2013..Establishment of a set of national health accounts will allow us as a society to understand which medical interventions improve the health of the U.S. population most efficiently. ..
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- Massachusetts Alzheimer's Disease Research CenterBradley T Hyman; Fiscal Year: 2013..Going forward, the MADRC will continue to expand its clinical and neuropathological resources, its innovative training and scientific programs directed toward AD research. ..
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- Alzheimer's Disease Research CenterMary Sano; Fiscal Year: 2013..abstract_text> ..
- Alzheimer's Disease Research CenterThomas J Montine; Fiscal Year: 2013..Montine;Project 2: Therapeutic Effects of Intra-Nasal Insulin Detemir, Dr. Suzanne Craft;Project 3: Modulation of A peptide accumulation and neuron damage in vivo with adult bone marrow transplants, Dr. C. Dirk Keene. ..
- Molecular Regulation of Microglia BehaviorGwenn A Garden; Fiscal Year: 2013....