Paul W. Buehler, PharmD, PhD

1995     Pharm.D., University of Illinois, Chicago                   

2002     Ph.D., Biopharmaceutical Sciences, University of Illinois, Chicago

Dr. Buehler is a pharmacologist and toxicologist who utilizes both applied and mechanistic approaches to understand red blood cell hemolysis and the downstream effects extracellular hemoglobin, heme and iron toxicity. His work focuses on genetic/acquired anemias as well as toxin and mechanical device induced hemolysis to characterize the genomic and proteomic changes in tissue that preempt or coincide with pathology.  This work has led to significant discoveries related to toxicant induced red blood cell damage following intravenous abuse of Opana ER.  This collaborative work with FDA has contributed to the recall of the deterrent formulated opiate, Opana ER (Oxymorphone HCl extended release) after a shift toward greater intravenous abuse and subsequently increased clinical cases of thrombotic microangiopathy and hemolytic uremic syndrome.

An important aspect of Dr. Buehler’s work is to identify ways to slow, reverse or prevent the effects of intra- and extra-vascular hemolysis induced pathobiology using plasma and recombinant constructs of haptoglobin, hemopexin and transferrin as well identifying methods to upregulate these proteins in states of acute and chronic depletion. The post-hemolysis molecular management of hemoglobin, hemin and iron are controlled by an efficient system of binding/transport proteins that ultimate target monocyte and macrophage cellular receptors (CD163, CD91, TfR1,2).  This system, and associated transport proteins, represent an important first line of defense against toxicity associated with hemolytic processes and offer several targets for therapeutic development.

Additionally, Dr. Buehler’s research interests include studying the effects of novel red blood cell processing techniques (pathogen reduction, innovative storage, stem cell derived and bioengineered red blood cells) on quality and function (post-transfusion recovery, oxygen delivery, intercellular gas exchange, and tissue metabolic response).  His work integrates experimental markers of post-transfusion response to oxygen homeostasis and erythropoiesis coupled with oxygen imaging techniques to understand the physiological impact of novel blood processing approaches. This work specifically evaluates post-transfusion changes in tissue blood flow and oxygen sensing and erythropoiesis at the molecular level, with a focus on the study of hypoxia inducible factors (HIF-1 and HIF-2), erythropoietin, erythroferrone and hepcidin.  His work optimizes promising oximetry and imaging techniques that measure tissue oxygen concentrations at multiple anatomical sites to complement the timing of molecular adaptive responses.

From a biopharmaceutical product development perspective, Dr. Buehler has an extensive knowledge base in pre-clinical therapeutics development with over fifteen years of regulatory integrated research experience as a pharmacologist in both the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research at the FDA. He has evaluated and guided industry, academic and other government-based sponsors on pre-clinical product development at pre-IND, IND, NDA and BLA stages on more than two hundred individual applications including multiple medical counter measures applications involving the animal rule.   Many of his experiences include product development guidance on vascular, coagulation, immune modulatory and transfusion-based therapeutics spanning from the pre-IND stage to NDA or BLA application and product licensure.  He has been involved in the review and approval of more than ten currently licensed products for the treatment of hereditary angioedema, hemophilia, thrombotic thrombocytopenic purpura, protein C deficiency, immune deficiencies and blood loss.

Boretti, F.S.*, Buehler, P.W.*, D’Agnillo, F., Kluge, K., Glaus, T., Butt, O.I., Jia, J, Pereira, C.P., Maggiorini, M., Schoedon, G., Alayash, A.I., and Schaer, D.J. Intravascular sequestration within the haptoglobin complex is effective in treating hypertensive and oxidative effects of plasma free hemoglobin. J Clin. Invest. 119(8):2271-80, 2009.

Gelderman M.P., Baek J.H., Yalamanoglu A., Puglia M., Vallelian F., Burla B., Vostal J., Schaer D.J., Buehler P.W. Reversal of hemochromatosis by apo-transferrin in non-transfused Hbbth3/+ (heterozygous b1/b2 globin gene deletion) mice.  Haematologica. 2015, 100 (5): 611-22.

Schaer C.A., Deuel J.W., Schildknecht D., Mahmoudi L., Garcia-Rubio I., Owczarek C., Schauer S., Kissner R., Banerjee U., Palmer A.F., Spahn D.R., Irwin D.C., Vallelian F., Buehler P.W., Schaer D.J. Haptoglobin preserves vascular nitric oxide signaling during hemolysis. Am J Respir Crit Care Med. 2016, 103 (10): 1111-1122.

Hunt R., Yalamanoglu A., Tumlin J., Schiller T., Baek J.H., Wu A., Fogo A.B., Yang H., Wong E., Miller P., Buehler P.W*., Kimchi-Sarfaty C. A mechanistic investigation of thrombotic microangiopathy associated with IV abuse of Opana ER. Blood. 2017, 16;129 (7):896-905.

Baek J.H., Yalamanoglu A., Gao Y., Guenster R., Spahn D.R., Schaer D.J., Buehler P.W. Iron accelerates hemoglobin oxidation increasing mortality in vascular diseased guinea pigs following transfusion of stored blood. JCI Insight. 2017 May 4;2(9).

Redinus K., Baek J.H., Yalamanoglu A., Shin H.K.H., Moldova R., Harral J.W., Swindle D., Pak D., Ferguson S.K., Nuss R., Hassell K., Nozik-Grayck E., Palmer A.F., Fini M.A., Karoor V., Stenmark K.R., Buehler P.W.*, Irwin D.C.* An Hb-mediated circulating macrophage contributing to pulmonary vascular remodeling in sickle cell disease. JCI Insight. 2019, Aug 8;4(15).

Hugelshofer M.​, Buzzi R.M.​, Schaer C.A.​ Richter H.​, Akeret K​., Anagnostakou V.​, Mahmoudi L.​, Vaccani R.​, Vallelian F.​, Deuel J​.,  Kronen PW​., Kulcsar Z​.,  Regli​ L.,  Baek J.H.​, Pires I.S.​, Palmer A.F.​,  Dennler M.​, Humar R.​,  Buehler P.W.​, Kircher P.R.​,  Keller E.​, Schaer, D.J. Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm. J Clin Invest. 2019 Oct 22. doi: 0.1172/JCI130630.

Stefanoni D, Shin HKH, Baek JH, Champagne DP, Nemkov T, Thomas T, Francis RO, Zimring JC, Yoshida T, Reisz JA, Spitalnik SL, Buehler PW*, D'Alessandro A*. Red blood cell metabolism in rhesus macaques and humans: comparative biology of blood storage. Haematologica. 2019 Nov 7. pii: haematol.2019.229930. doi: 10.3324/haematol.2019.229930.