Ph.D., University of Texas Medical School, Houston
Tel: (617) 552-2325
E-mail: frank.ivey.1@bc.edu
Fields of Interest
Chemical biology; signal transduction; fungal biology
Academic Profile
My research has focused on problems in basic and applied areas of biomedical research, including signal transduction in fungi, vaccine development for Valley Fever and more recently, the development and commercialization of a drug discovery platform that uses genetically engineered yeast strains to identify medicinal compounds.
1993-1999
My dissertation focused on understanding how fungi sense their surroundings by utilizing heterotrimeric G proteins; this class of evolutionarily conserved proteins is used by animals for sensing light (vision), odorants, and for taste, among many other sensing pathways. This work provided the first biochemical evidence that GNA-1, a Ga subunit from Neurospora crassa, was required to stimulate cAMP production through positive regulation of adenylate cyclase despite its classification as a member of the inhibitory class of Ga subunits that generally act as negative regulators.
1999-2002
In 1999, at the South Texas Center for Biotechnology in Medicine, with Drs. Rebecca Cox and Mitch Magee, I focused on developing a vaccine against the highly pathogenic fungus, Coccidioides immitis. During this postdoctoral fellowship, I isolated a fungal-specific gene, ELI-Ag1, which could protect mice against a lethal challenge with live C. immitis spores when administered as a DNA-based vaccine. The protective gene, ELI-Ag1, and the methods comprising its isolation have been filed with the United States Patent Office; this gene and its protein product are still under investigation for their potential as a Valley Fever vaccine.
2002-2006
In 2002, I began working with Dr. Charles Hoffman at Boston College, accepting a National Research Service Award from the NIH to take advantage of the tremendous techniques offered by yeast molecular biology and genetics to define structure-function relationships that govern the inter- and intra-molecular interactions necessary for G protein-mediated signal transduction. This work led to the identification of a Ga (Gpa2) binding site on the Schizosaccharomyces pombe adenylate cyclase enzyme. Although it remains to be determined how Gpa2 binding to adenylate cyclase results in effector activation, the elucidation of this activation mechanism should enhance our understanding of cAMP signaling in fungal pathogens, many of which utilize this signaling pathway to regulate virulence factors. This work was the first to describe a direct physical interaction between a Ga subunit and adenylate cyclase in any fungal system.
In a separate project, with the assistance of several undergraduate research assistants (Fran Taglia, Matt Ziparo, and Fan Yang), we carried out a genetic screen to isolate mutant alleles of Gpa2 that promoted Gbg-independent activation of the cAMP pathway. Subsequently, thirteen constitutively activated alleles of Gpa2 were identified and are currently being tested for both their in vivo and in vitro characteristics. These experiments promise to provide details into the mechanism of Ga activation and may uncover critical residues within Gpa2 that are required for its intrinsic GDP-GTP binding and hydrolysis properties and/or its interaction with other proteins. This single collection of constitutive Ga alleles outnumbers all other Ga activating mutations in the literature.
Predicted Structure of Gpa2 with bound GDP
This predicted model of Gpa2 is based on available crystal structure data from several Ga proteins. The lysine residue highlighted in white (K270) positions over the guanine nucleotide binding site (multicolored, space-filled molecule); presumably, it acts as a molecular clamp that acts to properly position guanosine nucleotides in the active site, as mutation of this residue (K270E) results in rapid loss of GDP and activation of Gpa2 through constitutive GTP occupancy.
2006-Present
Drug Discovery using Genetically-Engineered Fission Yeast
Using a panel of genetically engineered fission yeast strains, each expressing a unique mammalian PDE isoform, we (Charles Hoffman Lab Members) have developed a high throughput drug screen for compounds that inhibit or stimulate individual members of this large, complex family of PDE enzymes.
There are 11 families of PDEs in humans; each family is comprised of several genes that are further subdivided by unique splice variants, each encoding a specific isoenzyme. It is estimated that almost 100 unique PDEs co-exist in our bodies, distributed among different tissues, cell types and subcellular compartments. The shear number of PDE enzymes indicates the extraordinary tasks they must carry out.
Compounds that inhibit or stimulate PDE activity are sought for the treatment of anxiety, depression, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, schizophrenia, psychosis, sepsis, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, renal disease, stroke, rhinitis, psoriasis, memory loss, chronic lymphocytic leukemia, prostate cancer, thyroid disease, male hypogonadism, penile erectile dysfunction, cardiac disease, diabetes, obesity, multiple sclerosis, rheumatoid arthritis, osteoporosis and cystic fibrosis. In addition, drug compounds that target PDEs in pathogenic organisms (eg. Trypanosomal parasites) are also being sought, in hopes that they may prove beneficial in treating these infections.
Chemical inhibitor and activator screens that target PDEs are carried out at the Broad Institute and we are developing a panel of strains that express 20 different target enzymes. The breadth of this panel allows us to determine inhibitor/activator specificity and allows us to select lead compounds for downstream development. This screen has already allowed us to identify compounds with previously unrealized specificity. The recent identification of inhibitors that can differentiate between long and short forms of the same PDE (PDE4A5 vs. PDE4A1) highlights the power of this screening platform and approach. To date, we have performed PDE inhibitor/activator screens on several targets in parallel and have produced a dataset approaching half of a million points. Furthermore, we have developed strains and novel techniques that allow us to work with cGMP-specific PDEs despite the apparent absence of cGMP signaling in S. pombe.
PUBLICATIONS
Ivey, F.D., Wang, L., Demirbas, D.,
Kao, R.S., Morreale, E., Wang, L., Ivey, F.D., and Hoffman, C.S. “Schizosaccharomyces pombe Git1 is a C2-domain protein required for glucose activation of adenylate cyclase.” Genetics, 173:49-61, 2006.
Wang, L., Griffiths Jr., K., Zhang, Y.H., Ivey, F.D., and Hoffman, C.S. “Schizosaccharomyces pombe adenylate cyclase suppressor mutations suggest a role for cAMP phosphodiesterase regulation in feedback control of glucose/cAMP signaling.” Genetics, 171:1523-33, 2005.
Ivey, F.D. and Hoffman, C.S. “Direct activation of fission yeast adenylate cyclase by the Gpa2 Ga of the glucose signaling pathway.” Proc Natl Acad Sci USA. 102(17):6108-13, 2005.
Wang, L., Kao, R., Ivey, F.D., and Hoffman, C.S. “Strategies for gene disruptions and plasmid constructions in fission yeast.” Methods 33(3):199-205, 2004.
Ivey, F.D., Magee, D.M., Woitaske, M.D.,
Ivey, F.D. and Hoffman, C.S. “Pseudostructural inhibitors of G protein signaling during development.” Developmental Cell, (Preview) 3(2): 154-5, 2002.
Jiang, C., Magee, D.M., Ivey, F.D., and Cox, R.A. “Role of signal sequence in vaccine-induced protection against experimental coccidioidomycosis.” Infection and Immunity 70(7):3539-45, 2002.
Ivey, F.D., Kays, A.M., and Borkovich, K.A. “Shared and independent roles for a Gai protein and adenylyl cyclase in regulating development and stress responses in Neurospora crassa." Eukaryotic Cell. 1(4):634-642, 2002.
Ivey, F.D., Yang, Q., and Borkovich, K.A. “Positive regulation of adenylyl cyclase activity by a Gai homologue in Neurospora crassa.” Fungal Genetics and Biology 26:48-61, 1999.
Ivey, F.D., Hodge, P.N., Turner, G.E., and Borkovich, K.A. “The Gai homologue gna-1 controls multiple differentiation pathways in Neurospora crassa.” Molecular Biology of the Cell 7:1283-1297, 1996.
AWARDS
“Genetic analysis of G protein signaling in Schizosaccharomyces pombe.” Individual National Research Service Award, NIH, 2003-2006
“Genetic manipulation of Coccidioides immitis through electroporation.” $10,000 award from the Ewing Halsell Foundation, 2000
PATENTS
“Compositions and Methods Comprising a Protective Antigen of Coccidioides immitis.” R.A. Cox, D.M. Magee, F.D. Ivey, and M.D. Woitaske. Number EV 336 531 264 US. Filed 11/10/2004 in the
60/919,125 “Compositions and Methods for Identifying Inhibitors and Activators of cyclic-GMP Phosphodiesterases.” F. Douglas Ivey and Charles S. Hoffman.
| Return to Faculty List | Biology Home | Graduate Studies |