Profile Heather Knowles

Summary of Research:

TRPM2 is a member of the transient receptor potential melastatin-related (TRPM) family of cation channels. It is unique among all known ion channels in that the gating domain (responsible for opening the pore) is an apparent fusion of an enzyme to an ion channel. This C-terminal gating domain has significant homology with NudT9, a specific ADP-ribose hydrolase. As a result, cytoplasmic ADP-ribose activates cation entry through the plasma membrane. In addition, oxidants such as H2O2 indirectly trigger activation of TRPM2 mediated calcium entry.

Enzymes called NAD glycohydrolases, which hydrolyze the nicotinamide group from NAD molecules, generate ADPR. Glycohydrolase activity has been measured in the mitochondria, in the nucleus by PARP/PARG enzymes and by CD38, an ectoenzyme found differentially expressed on all hematopoietic cells.

The presence of a novel signaling pathway involving intracellular oxidants, ADP-ribose, TRPM2 and intracellular calcium is an exciting possibility in immune cells. There is mounting evidence for oxidants as messengers in signaling, and an established role for calcium signaling by other metabolites of NAD+ hydrolysis. CD38 deficiency in mice leads to defects in cell migration and antibody responses, presumably through a loss of cyclicADP-ribose signaling. However, the function of monomeric ADPR and signaling through TRPM2 is still unclear. My thesis project has been focused on understanding the function of this rare cation channel in the development, activation and function of immune cells.

Awards/Publications:

Selected Mini Symposia Speaker, 13th International Congress of Immunology, Rio de Janeiro, Brazil, 2007

Graduate Student Poster Award, Department of Immunology Conference, UCD & NJC, 2006

National Institutes of Health Training Grant, 2002-2005

Perraud AL, Takanishi CL, Shen B, Kang S, Smith MK, Schmitz C, Knowles HM, Ferraris D, Li W, Zhang J, Stoddard BL, Scharenberg AM. Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels. J Biol Chem. 2005 Feb 18; 280(7): 6138

Perraud AL, Knowles HM, Schmitz C. Novel aspects of signaling and ion-homeostasis regulation in immunocytes. The TRPM ion channels and their potential role in modulating the immune response. Mol Immunol. 2004 Jul; 41(6-7): 657-73.

Cipriani B, Chen L, Hiromatsu K, Knowles H, Raine CS, Battistini L, Porcelli SA, Brosnan CF. Upregulation of group 1 CD1 antigen presenting molecules in guinea pigs with experimental autoimmune encephalomyelitis: an immunohistochemical study. Brain Pathol. 2003 Jan; 13(1): 1-9.

Cipriani B, Knowles H, Chen L, Battistini L, Brosnan CF. Involvement of classical and novel protein kinase C isoforms in the response of human V gamma 9V delta 2 T cells to phosphate antigens. J Immunol. 2002 Nov 15; 169(10): 5761-70.

Cipriani B, Borsellino G, Knowles H, Tramonti D, Cavaliere F, Bernardi G, Battistini L, Brosnan CF. Curcumin inhibits activation of Vgamma9Vdelta2 T cells by phosphoantigens and induces apoptosis involving apoptosis-inducing factor and large scale DNA fragmentation. J Immunol. 2001 Sep 15; 167(6): 3454-62.

Downen M, Belkowski S, Knowles H, Cardillo M, Prystowsky MB. Developmental expression of voltage-gated potassium channel beta subunits. Dev Brain Res. 1999 Oct 20; 117(1): 71-80.