Prostaglandin signaling following seizures

Summary

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

Top Publications

  1. pmc Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection
    Jianxiong Jiang
    Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA
    Trends Pharmacol Sci 34:413-23. 2013
  2. pmc Cyclooxygenase-2 in epilepsy
    Asheebo Rojas
    Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, U S A
    Epilepsia 55:17-25. 2014
  3. pmc Lead optimization studies of cinnamic amide EP2 antagonists
    Thota Ganesh
    Department of Pharmacology, School of Medicine, Emory University, 1510 Clifton Road, Atlanta, Georgia 30322, United States
    J Med Chem 57:4173-84. 2014
  4. pmc Development of second generation EP2 antagonists with high selectivity
    Thota 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

Research Grants

Detail Information

Publications5

  1. pmc Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection
    Jianxiong 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. ..
  2. pmc Cyclooxygenase-2 in epilepsy
    Asheebo Rojas
    Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, U S A
    Epilepsia 55:17-25. 2014
    ....
  3. pmc Lead optimization studies of cinnamic amide EP2 antagonists
    Thota 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. ..
  4. pmc Development of second generation EP2 antagonists with high selectivity
    Thota 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. ..

Research Grants30

  1. MOLECULAR AND CELLULAR MECHANISMS OF OSTEOPOROSIS
    Stavros C Manolagas; Fiscal Year: 2013
    ....
  2. CNS injury caused by HIV-1 and alcohol: Protective effects of CB2 activation
    Yuri Persidsky; Fiscal Year: 2013
    ..abstract_text> ..
  3. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  4. The Functional Significance of Conformational States in Glutamatergic Signaling
    CATHERINE LOURDES SALUSSOLIA; Fiscal Year: 2013
    ..Thus, by defining novel aspects of glutamate receptor structure-function my studies will serve to further understand glutamate receptor gating and may lead to novel strategies to treat glutamate-based neurological diseases. ..
  5. Macrophages, NR2B-containing NMDA Receptors and HIV Dementia
    HUANGUI HANK XIONG; Fiscal Year: 2013
    ....
  6. Endogenous GABAergic Activity
    Istvan Mody; Fiscal Year: 2013
    ..abstract_text> ..
  7. Expanding the National Health Accounts
    David 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. ..
  8. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  9. Glutaminase: neurotoxic link in HIV-1 Associated Dementia
    JIALIN CHARLES ZHENG; Fiscal Year: 2013
    ..This work will elucidate mechanisms through which glutaminase play in neuronal injury during HAND, which could identify new therapeutic strategies for treating HAND and other neurodegenerative disorders. ..
  10. Massachusetts Alzheimer's Disease Research Center
    Bradley 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. ..
  11. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013
    ..These studies will establish principles and protocols directly applicable to subsequent human clinical trials. ..
  12. THE CDK5/P35 KINASE
    Li Huei Tsai; Fiscal Year: 2013
    ....
  13. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  14. Alzheimer's Disease Research Center
    Mary Sano; Fiscal Year: 2013
    ..abstract_text> ..
  15. Alzheimer's Disease Research Center
    Thomas 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. ..
  16. Molecular Regulation of Microglia Behavior
    Gwenn A Garden; Fiscal Year: 2013
    ....