Donald L. Granger

Donald L. Granger, MD

Languages spoken: English

Academic Information

Departments Primary - Internal Medicine

Divisions: Infectious Diseases

Board Certification

  • American Board of Internal Medicine (Internal Medicine)
  • American Board of Internal Medicine (Sub: Infectious Disease)

Research Statement

The pathogenesis of cerebral malaria (CM) is poorly understood. We discovered that Tanzanian children with CM have markedly low plasma levels of arginine (Arg) and markedly elevated phenylalanine (Phe). Arg is needed for synthesis of nitric oxide (NO) by NO synthases (NOS). NO is an important post-synaptic modulator of neurons in the brain. Phe, through its metabolic product, tyrosine (Try), is the substrate for the biogenic amine neurotransmitters (BAN), dopamine, epinephrine and norepinephrine. Enzymes for NO, Tyr and DOPA (precursor of dopamine) synthesis requires the cofactor, tetrahydrobiopterin (BH4). Supply of BH4 during infection is augmented by gamma interferon-induced transcription of GTP cyclohydrolase (GTPCH), the key regulatory enzyme for entrance into this pathway. We have evidence that this response is suppressed in CM. Because of the critical roles of Arg, Phe, NO and BAN in normal brain function, inhibition of synthesis may impact CM pathogenesis. We hypothesize that children with CM are deficient in BH4, that BH4 deficiency causes elevated Phe levels, and that BH4 deficiency causes elevated Phe levels, and that BH4 deficiency in the CNS limits synthesis of BAN leading to brain pathology.

The specific aims are: (1) Determine if children with CM have low systemic levels of BH4; (2) determine if there is CNS deficiency of BH4 and BAN; and (3) whether BH4 deficiency is associated with decreased GTPCH transcription and enzyme activity. In a controlled prospective study, children with CM will donated blood, urine and CSF for measurements of BH4 and BAN metabolites, which will be correlated with clinical status and outcome. Their peripheral blood mononuclear cells will be used to do RT-PCR and immunoblots for GTPCH mRNA and protein.

If the hypotheses are correct, it may be possible to alter CNS disease by administering precursors for BH4 and BAN. Thus the project may lead to rapid translation into trials for management of children with CM.

Education History

Undergraduate University of Utah
 BA
Graduate Training University of Rochester
 MS
Professional Medical University of Utah Hospital School of Medicine
 MD
Internship Strong Memorial Hospital
 Intern
Residency Strong Memorial Hospital
 Resident
Fellowship University of Utah School of Medicine
 Fellow
Research Fellow Johns Hopkins University School of Medicine
 Research Fellow

Selected Publications

Journal Article

  1. Levesque MC, Hobbs MR, O'Loughlin CW, Chancellor JA, Chen Y, Tkachuk AN, Booth J, Patch KB, Allgood S, Pole AR, Fernandez CA, Mwaikambo ED, Mutabingwa TK, Fried M, Sorensen B, Duffy PE, Granger DL, Anstey NM, Weinberg J (2010). Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes. Human genetics, 127(2), 163-82. (Read full article)
  2. Yeo TW, Lampah DA, Tjitra E, Gitawati R, Kenangalem E, Piera K, Granger DL, Lopansri BK, Weinberg JB, Price RN, Duffull SB, Celermajer DS, Anstey N (2009). Relationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavailability and perfusion in severe falciparum malaria. The Journal of infectious diseases, 200(10), 1522-9. (Read full article)
  3. Randall LM, Kenangalem E, Lampah DA, Tjitra E, Mwaikambo ED, Handojo T, Piera KA, Zhao ZZ, de Labastida Rivera F, Zhou Y, McSweeney KM, Le L, Amante FH, Haque A, Stanley AC, Woodberry T, Salwati E, Granger DL, Hobbs MR, Price RN, Weinberg JB, Montgomery GW, Anstey NM, Engwerda C (2010). Age-related susceptibility to severe malaria associated with galectin-2 in highland Papuans. The Journal of infectious diseases, 202(1), 117-24. (Read full article)
  4. Granger DL, Lopansri BK, Butcher D, Wong S, Tavkoli NP, Backenson PB, Campbell M, Fine A, Ackelsberg J, Freedman A, Fink M, Artsob H, Holbrook MR, DeBiasi RL, Waterman PE, Rollin PE, MacNeil A, Panella AJ, Kosoy O, Lanciotti RS, Campbell GL, Staples JE, Fisher M, Gibney KB, Knust (2010). Tick-Borne Encephalitis Amount U.S. Travelers to Eurpoe and Asia --- 2000--2009. MMWR. Morbidity and mortality weekly report, 59(11), 335-338.
  5. Weinberg JB, Lopansri BK, Mwaikambo E, Granger D (2008). Arginine, nitric oxide, carbon monoxide, and endothelial function in severe malaria. Current opinion in infectious diseases, 21(5), 468-75. (Read full article)
  6. Yeo TW, Lampah DA, Tjitra E, Gitawati R, Darcy CJ, Jones C, Kenangalem E, McNeil YR, Granger DL, Lopansri BK, Weinberg JB, Price RN, Duffull SB, Celermajer DS, Anstey N (2010). Increased asymmetric dimethylarginine in severe falciparum malaria: association with impaired nitric oxide bioavailability and fatal outcome. PLoS pathogens, 6(4), e1000868. (Read full article)
  7. Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, Granger DL, Weinberg JB, Lopansri BK, Price RN, Celermajer DS, Duffull SB, Anstey N (2008). Safety profile of L-arginine infusion in moderately severe falciparum malaria. PloS one, 3(6), e2347. (Read full article)

Abstract

  1. Mukemba J, Sangu W, Mchomvu F, Rubach M, Lopansri B, Yeo T, Anstey N, Weinberg JB, Granger DL, Mwaikambo (2009). Increased urine pterins in children with uncomplicated falciparum malaria and hyperphenylalaninemia.
  2. Mukemba JP, Florence S, Sangu W, Mchomvu F, Rubach M, Lopansri BK, Yeo TW, Anstey NM, Weinberg JB, Granger DL, Mwaikambo E (2010). Elevated levels of CSF tetrahydrobiopterin distinguish non-malarial coma from cerebral malaria with high specificity and sensitivity.
  3. Mwaikambo ED, Mukemba J, Sangu W, Mchomvu F, Rubach M, Lopansri B, Yeo T, Anstey N, Weinberg JB, Granger D (2010). Abnormal brain pterin metabolism in children with cerebral malaria.