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William F. Carson IV, Ph.D.
e-mail address: wfcarson@umich.edu

Mentor: Steven Kunkel, Ph.D.


Techniques Used
:

Cecal Ligation and Puncture, Flow Cytometry, Cell sorting (FACS/Beads), Cell Culture, RNA/DNA Isolation, RT-PCR, Thymidine Proliferation, Adoptive Transfer / Bone Marrow Chimeras, Chromatin Immunoprecipitation, Animals models of allergic and granulomatous lung inflammation, multiplex protein analysis, mRNA/miRNA superarray analysis


Research Description:

Immune dysregulation following severe sepsis is a significant human health concern. Survivors of the severe, acute inflammatory response following sepsis are at increased risk of mortality due to nonseptic causes, including an increased susceptibility to opportunistic infections. Recent studies utilizing animal models of severe sepsis indicate that the suppression of immune function following severe septic shock is due to long-term silencing of proinflammatory genes through epigenetic mechanisms. Specifically, methylation of histone proteins involved with regulation of the proinflammatory cytokine interleukin(IL)-12 following severe sepsis results in silencing of Il12 gene loci and an impaired capacity to develop protective T-helper type-1 (T H 1) responses in vivo . This results in an immunosuppressive phenotype, manifested by the susceptibility of mice subjected to the sepsis model of cecal ligation and puncture (CLP) to the opportunistic pathogen Aspergillus fumigatus . Therefore, studies involving CLP can be used to investigate the specific cellular and molecular mechanisms governing immunsuppression in humans following severe sepsis.

My work in the Kunkel lab involves studying the role of epigenetic modifications in governing the immunosuppressive phenotype following severe sepsis. My research focuses on four specific areas:

•  Identifying the role of epigenetic modifications in the generation of T-helper subtypes (T H 1, T H 2, T H 17, T reg ) following CLP, specifically in regards to the T H skewing observed in peripheral T cells following septic shock,

•  Investigating the role of gene regulation in the function of antigen-presenting cells following severe sepsis, including their ability to properly process and present antigen to T cells,

•  Elucidating the effect of severe sepsis on bone marrow progenitor cells, including lymphocyte and granulocyte/monocyte progenitors, to determine if the defects in mature immune cells are due to gene dysregulation at the level of the stem cell,

•  Determining the ability of specific chemokines and cytokines produced during the “cytokine storm” of severe sepsis to generate epigenetic modifications in hematopoietic cells, including bone marrow progenitors, innate and adaptive immune cells.


Publications:

Singh, A., Carson IV, W. F., Secor Jr., E. R., Guernsey, L. A., Flavell, R. A., Clark, R. B., Thrall, R. S., Schramm, C. M. (2008) Regulatory role of B cells in a murine model of allergic airway disease. J. Immunol. 180(11)7318-7326.

Singh, A., Thrall, R.S., Guernsey, L.A. , Carson IV, W. F., Secor Jr., E. R, Cone, R. E., Rajan, T.V., Schramm, C. M. (2008) Subcutaneous late phase responses are augmented during local inhalational tolerance in a murine asthma model. Immunol. Cell Bio. 86(6)535-538.

Carson IV, W. F. , Guernsey , L. A., Singh, A., Vella, A. T., Schramm, C. M., Thrall, R. S. (2007) Accumulation of regulatory T cells in local draining lymph nodes of the lung correlates with spontaneous resolution of chronic asthma in a murine model. Int. Arch. Allergy Immunol. 145(3)231-243.

Secor Jr., E. R., Carson IV, W. F. , Singh, A., Pensa, M., Guernsey , L. A., Schramm, C. M., and Thrall, R. S. (2007) Oral bromelain attenuates inflammation in an ovalbumin-induced murine model of asthma. Evid. Based Complement. Altern. Med. Online Advanced Access (3-14-2007)

Kabbur, P. M., Carson IV., W. F. , Guernsey L. A., Secor Jr., E. R., Thrall, E. R., Schramm, C. M. (2006) Interleukin-10 does not mediate inhalational tolerance in a chronic model of ovalbumin-induced allergic airway disease. Cell Immunol. 239(1)67-74.

Secor Jr., E. R., Carson IV., W. F. , Cloutier, M. M., Guernsey , L. A., Schramm, C. M., Wu, C. A., Thrall, R. S. (2005) Bromelain exerts anti-inflammatory effects in an ovalbumin-induced murine model of allergic airway disease. Cell Immunol. 237(1)68-75.

 

Awards:

 


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