Walter H.A. Kahr
MD, University of Toronto, 1994
PhD, University of Toronto, 1994
Postdoc, McMaster University, 1999-2002
|Address||The Hospital for Sick Children
PGCRL, Rm 19.9714
686 Bay Street
Toronto, ON M5G 0A4
|Lab Phone||416-813-7654 ext 328019 or 328018|
I received my MD and PhD (Biochemistry) from the University of Toronto in 1994. Following post-graduate training in Internal Medicine at the University of Toronto (1994-1997), I completed a hematology fellowship in the Department of Medicine (1997-1999) and a post-doctoral fellowship in the Department of Pathology and Molecular Medicine (1999-2002) at McMaster University in Hamilton. During my post-doctoral fellowship I discovered that bleeding problems in patients with the rare inherited Québec platelet disorder arose from the abnormal expression of urokinase in their platelets. This information aided the effective treatment of this bleeding disorder. As a clinician-scientist at the Hospital for Sick Children I follow children with bleeding and clotting disorders. My research is focused on understanding the structure and function of platelets – the smallest cells in the blood – and how they develop from megakaryocytes, the largest cells in the bone marrow.
My lab is located within the SickKids Research Institute Program in Cell Biology on the 19th floor of the new PGCRL building located on Bay St. in downtown Toronto.
Fred G. Pluthero, Lab Research Project Manager
Ling Li, Lab Research Project Coordinator
Richard Leung, Electron Microscope Technician
Ruth Milkereit, Post Doctoral Fellow
Richard W. Lo, Graduate Student
Marko Drobac, Graduate Sudent
Carrie Chan Cheng, Graduate Student
Kevin To, Graduate Student
Structure and Function of Platelets and Their Development from Megakaryocytes
Megakaryocyte and platelet development and function
Humans produce 100 billion platelets per day, making them the second most common cell in the bloodstream. Platelets patrol the vasculature for sites of injury, where they adhere, aggregate and activate allowing the formation of clots to limit blood loss. Thus individuals lacking platelets or having dysfunctional cells experience abnormal bleeding. In addition to their key role in blood clotting, platelets are also involved in development, inflammation, wound healing, cancer progression, pathogen defense and liver regeneration, and the pathological role of platelets during acute coronary syndromes and stroke has long been recognized. Platelets have also been implicated in the development of atherosclerosis, where several inflammatory mediators – chemokines and chemoattractants – stored and released from platelet α‑granules can contribute to the progression of atherosclerotic lesions. Insights into the development and function of platelets have been gained by studying patients with inherited platelet function disorders, including a number of discoveries from my lab.
Platelets are produced by megakaryocytes, and we study this process both in vivo in animal models and in vitro in cultures of mouse or human cells, where we can monitor gene expression, physical changes and the effects of mutations using methods such as high-resolution fluorescence and electron microscopy. Primary human megakaryocytes are grown from hematopoietic CD34+ stem cells in a serum-free culture system, allowing us to look at protein expression during development and determine which proteins are synthesized endogenously by megakaryocytes or taken up from plasma through endocytotic mechanisms. For example we showed that complement factor H is endogenously synthesized by human megakaryocytes and is not localized in granular compartments within platelets.
Absent platelet alpha granules in ARC syndrome patients
We have extensively studied patients with arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, whose platelets lack secretory α-granules. We initially linked this condition to the absence of functional VPS33B protein. Subsequent studies using yeast two-hybrid screens and mass spectrometry determined that VPS33B interacts with VPS16B to form a complex. We showed that VPS16B is also required for platelet α-granule biogenesis where mutations in VPS16B also cause ARC syndrome. We are currently investigating how the VPS33B-VPS16B complex facilitates α-granule biogenesis in megakaryocytes.
The BEACH protein NBEAL2 is required for platelet alpha granule formation
Through a collaborative effort using classical genetics and platelet mRNA expression analysis, we were one of 3 groups to discover that mutations in NBEAL2 (neurobeachin-like 2) cause the inherited platelet function disorder gray platelet syndrome (GPS). NBEAL2 encodes a multi-domain protein with unknown function. We have generated Nbeal2-/- mice that recapitulate human GPS with a bleeding phenotype, macrothrombocytopenia, α-granule-deficient platelets, platelet dysfunction and splenomegaly. Studies of Nbeal2-/- mice and their cultured megakaryocytes demonstrated impaired megakaryopoiesis. We are currently extending these studies by investigating the molecular mechanisms that govern α-granule biogenesis by determining the structure and function of NBEAL2. These studies have important implications for understanding the mechanism of megakaryocyte and platelet α-granule biogenesis.
Awards & Distinctions
1999-2001 — Medical Research Council/HSFC Post Doctoral Fellowship Award
2001-2002 — Heart and Stroke Foundation of Canada Post Doctoral Fellowship Award
2006-2009 — Heart and Stroke Foundation of Ontario, Phase II Clinician Scientist Award
View all publications on PubMed
Inherited macrothrombocytopenias on the rise.
Landolt-Marticorena C, Kahr WH.
Blood. 2014 Oct 16;124(16):2473-5. Read
Abnormal megakaryocyte development and platelet function in Nbeal2(-/-) mice.
Kahr WH, Lo RW, Li L, Pluthero FG, Christensen H, Ni R, Vaezzadeh N, Hawkins CE, Weyrich AS, Di Paola J, Landolt-Marticorena C, Gross PL.
Blood. 2013 Nov 7;122(19):3349-58. Read
The VPS33B-binding protein VPS16B is required in megakaryocyte and platelet α-granule biogenesis.
Urban D, Li L, Christensen H, Pluthero FG, Chen SZ, Puhacz M, Garg PM, Lanka KK, Cummings JJ, Kramer H, Wasmuth JD, Parkinson J, Kahr WH.
Blood. 2012 Dec 13;120(25):5032-40. Read
Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome.
Kahr WH, Hinckley J, Li L, Schwertz H, Christensen H, Rowley JW, Pluthero FG, Urban D, Fabbro S, Nixon B, Gadzinski R, Storck M, Wang K, Ryu GY, Jobe SM, Schutte BC, Moseley J, Loughran NB, Parkinson J, Weyrich AS, Di Paola J.
Nat Genet. 2011 Jul 17;43(8):738-40. Read
Platelet-associated complement factor H in healthy persons and patients with atypical HUS.
Licht C, Pluthero FG, Li L, Christensen H, Habbig S, Hoppe B, Geary DF, Zipfel PF, Kahr WH.
Blood. 2009 Nov 12;114(20):4538-45. Read
Granules and thrombus formation.
Blood. 2009 Jul 30;114(5):932-3. Read
Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet alpha-granule biogenesis.
Lo B, Li L, Gissen P, Christensen H, McKiernan PJ, Ye C, Abdelhaleem M, Hayes JA, Williams MD, Chitayat D, Kahr WH
Blood. 2005 Dec 15;106(13):4159-66. Read