Rahima Zennadi, PhD

Associate Professor in Medicine
Campus mail 337MED Sci Res Bldg, Durham, NC 27710
Phone (919) 684-5378
Email address zenna001@mc.duke.edu

Sickle Cell Disease

My research investigations in Hematology address the disorders associated with abnormalities affecting cell membrane proteins involved in cell-cell interactions and their role in sickle cell vasculopathy. In sickle cell disease (SCD), recurrent obstruction of the microvasculature leads to serious life-threatening complications such as acute pain crises, acute chest syndrome, kidney failure and cerebrovascular accidents triggered by ischemic injury in multiple organs. Vascular occlusion is caused largely by adherence of sickle red blood cells and leukocytes to the vascular endothelium.  Prevention and reversal of established vascular occlusion in sickle cell patients are still a therapeutic challenge. We are testing the hypothesis that vascular occlusion-dependent leukocyte and endothelial cell (EC) activation and inflammation leads to the increased ischemic oxidative stress and subsequent oxidative tissue injury. We propose that generation of ischemic oxidative stress, via activation of various abnormal signaling mechanisms, creates a positive feed-back loop that further enhances vaso-occlusion, endothelial activation and inflammation in the vasculature in general, and in particular, in the brain, kidney and lung vessels. We believe that targeting these signaling mechanisms will not only have anti-vaso-occlusive effects, but may also reduce inflammation and ischemic oxidative stress-induced endothelial dysfunction. In addition, we are also investigating signaling mechanisms activated by stress erythropoiesis during erythroid cell proliferation and maturation in sickle cell disease.

Malaria

Up to 15 to 20% of patients with falciparum malaria die despite our best malaria treatments. We clearly need more effective treatments than current anti-malarial drugs alone provide. Adherence of Plasmodium falciparum-infected red blood cells is at the core of the pathophysiology of severe malaria, and could lead to abnormal endothelial function, a process also central to the pathology of severe malaria. Using unique set of pharmacologic tools we are trying to elucidate the signaling mechanisms leading to infected red cell adherence to the vascular endothelium and the effects of these mechanisms on the vascular endothelium, and how best to target the parasite Plasmodium falciparum for treatment of malaria.

Education and Training

  • Ph.D., University of Nantes (France), 1992
  • M.S., University of Nantes (France), 1989

Publications

Telen, MJ, Batchvarova, M, Shan, S, Bovee-Geurts, PH, Zennadi, R, Leitgeb, A, Brock, R, and Lindgren, M. "Sevuparin binds to multiple adhesive ligands and reduces sickle red blood cell-induced vaso-occlusion." British journal of haematology 175, no. 5 (December 2016): 935-948.

PMID
27549988
Full Text

Zhao, Y, Schwartz, EA, Palmer, GM, and Zennadi, R. "MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease." FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30, no. 3 (March 2016): 1171-1186.

PMID
26631480
Full Text

Chiou, E, and Zennadi, R. "Gαs proteins activate p72(Syk) and p60-c-Src tyrosine kinases to mediate sickle red blood cell adhesion to endothelium via LW-αvβ3 and CD44-CD44 interactions." The international journal of biochemistry & cell biology 65 (August 2015): 40-51.

PMID
26007235
Full Text

Zennadi, R. "MEK Inhibitors, Novel Anti-Adhesive Molecules, Reverse Sickle Red Blood Cell Adhesion and Vaso-Occlusion in Vivo." BLOOD 124, no. 21 (December 6, 2014).

Scholars@Duke

Zennadi, R. "MEK inhibitors, novel anti-adhesive molecules, reduce sickle red blood cell adhesion in vitro and in vivo, and vasoocclusion in vivo." PloS one 9, no. 10 (January 2014): e110306-.

PMID
25330306
Full Text

Batchvarova, M, Shan, S, Zennadi, R, Lindgren, M, Leitgeb, A, Tamsen, PS, and Telen, MJ. "Sevuparin Reduces Adhesion Of Both Sickle Red Cells and Leukocytes To Endothelial Cells In Vitro and Inhibits Vaso-Occlusion In Vivo." November 15, 2013.

Scholars@Duke

Soderblom, EJ, Thompson, JW, Schwartz, EA, Chiou, E, Dubois, LG, Moseley, MA, and Zennadi, R. "Proteomic analysis of ERK1/2-mediated human sickle red blood cell membrane protein phosphorylation." Clinical proteomics 10, no. 1 (January 3, 2013): 1-.

PMID
23286773
Full Text

Terman, DS, Viglianti, BL, Zennadi, R, Fels, D, Boruta, RJ, Yuan, H, Dreher, MR, Grant, G, Rabbani, ZN, Moon, E, Lan, L, Eble, J, Cao, Y, Sorg, B, Ashcraft, K, Palmer, G, Telen, MJ, and Dewhirst, MW. "Sickle erythrocytes target cytotoxics to hypoxic tumor microvessels and potentiate a tumoricidal response." PLoS One 8, no. 1 (2013): e52543-.

PMID
23326340
Full Text

De Castro, LM, Zennadi, R, Jonassaint, JC, Batchvarova, M, and Telen, MJ. "Effect of propranolol as antiadhesive therapy in sickle cell disease." Clin Transl Sci 5, no. 6 (December 2012): 437-444.

PMID
23253664
Full Text

Zennadi, R. "Therapeutic Benefit of Small Molecule Inhibitors of MEK/ERK in Reducing Sickle Red Cell Adhesion and Vaso-Occlusion in Vivo." November 16, 2012.

Scholars@Duke

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