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.

Public Health Relevance

Acute brain attacks such as seizure induce severe brain inflammation and injury;however, the underlying causes are poorly understood. The research proposed in this application will provide innovative insights on the regulation of inflammation and injury in epileptic brain and might guide the efforts aimed at developing novel therapeutic strategies to treat chronic inflammation-associated neurological disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Career Transition Award (K99)
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NST-2 Subcommittee (NST)
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Whittemore, Vicky R
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Emory University
Schools of Medicine
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Ganesh, Thota; Jiang, Jianxiong; Dingledine, Ray (2014) Development of second generation EP2 antagonists with high selectivity. Eur J Med Chem 82:521-35
Rojas, Asheebo; Jiang, Jianxiong; Ganesh, Thota et al. (2014) Cyclooxygenase-2 in epilepsy. Epilepsia 55:17-25
Ganesh, Thota; Jiang, Jianxiong; Yang, Myung-Soon et al. (2014) Lead optimization studies of cinnamic amide EP2 antagonists. J Med Chem 57:4173-84
Jiang, Jianxiong; Dingledine, Ray (2013) Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection. Trends Pharmacol Sci 34:413-23
Ganesh, Thota; Jiang, Jianxiong; Shashidharamurthy, Rangaiah et al. (2013) Discovery and characterization of carbamothioylacrylamides as EP2 selective antagonists. ACS Med Chem Lett 4:616-621