Our general goal is to investigate the mechanism by which selected bioactive peptides: gonadotropin releasing factor (GnRH), inhibin, activin and follistatin and possibly other families of peptides including corticotropin releasing factor and vasopressin/oxytocin, act on their respective receptors in different tissues to modulate reproductive functions either pharmacologically or physiologically. We plan to synthesize the appropriate peptide/proteins and fragments thereof that will allow us to answer such questions. Long acting analogs, specific antibodies and antagonists as well as selectively labeled probes will be synthesized. More specifically, GNRH analogs of the fragments that are recognized to have behavioral effects on lordosis will be designed and synthesized in an effort to better define the specific receptor responsible for this action. In order to gain a better appreciation of the pharmacology and physiology of activin, we propose to characterize its secondary structure through a collaborative effort encompassing the analytical tools available in Core C and our ability to synthesize model peptides. We hope to be able to derive from this knowledge, the structure of the active core of activin and be in a better position to design activin and possibly inhibin competitive antagonists. Computer simulations will be used for the establishment of hypothetical tertiary structures which will be tested through the synthesis of constrained analogs. The synthesis of whole domains of follistatin will be attempted. Because of the unavailability of native and synthetic replicates with follistatin activity, a well characterized peptide with as little as 1% the potency of follistatin would be of great significance. Because the structure of inhibin may well be one order of magnitude more elaborate than that of activin, we only propose here to synthesize those fragments of the alpha-chain that will help in the development of selective RIAs. Different approaches for characterization of receptors of the hypothalamic releasing factors are being investigated by Project I in collaboration with Cores C, D and E. Upon identification of the GNRH, activin, inhibin or follistatin receptors, we will synthesize partial sequences for the development of specific antibodies. Ultimately, we would like to identify the active site of these receptors and study their interaction with their respective ligands. This task should be facilitated with the availability of highly potent bicyclic GNRH antagonists developed in part under the aegis of this grant. Finally, large quantities of one or two selected GNRH antagonists will be synthesized for collaborative clinical investigations not directly related to the control of reproduction such as treatment of sex steroid dependant cancers (prostate, brain and others) and endometriosis. This includes filing a Master File with the FDA.
| Muenster, Uwe; Korupolu, Radhika; Rastogi, Ratindra et al. (2011) Antagonism of activin by activin chimeras. Vitam Horm 85:105-28 |
| Kim, Meejung; Choe, Senyon (2011) BMPs and their clinical potentials. BMB Rep 44:619-34 |
| Valera, Elvira; Isaacs, Michael J; Kawakami, Yasuhiko et al. (2010) BMP-2/6 heterodimer is more effective than BMP-2 or BMP-6 homodimers as inductor of differentiation of human embryonic stem cells. PLoS One 5:e11167 |
| Isaacs, Michael J; Kawakami, Yasuhiko; Allendorph, George P et al. (2010) Bone morphogenetic protein-2 and -6 heterodimer illustrates the nature of ligand-receptor assembly. Mol Endocrinol 24:1469-77 |
| Looyenga, Brendan D; Wiater, Ezra; Vale, Wylie et al. (2010) Inhibin-A antagonizes TGFbeta2 signaling by down-regulating cell surface expression of the TGFbeta coreceptor betaglycan. Mol Endocrinol 24:608-20 |
| Hassold, Terry; Hunt, Patricia (2009) Maternal age and chromosomally abnormal pregnancies: what we know and what we wish we knew. Curr Opin Pediatr 21:703-8 |
| Wiater, Ezra; Lewis, Kathy A; Donaldson, Cynthia et al. (2009) Endogenous betaglycan is essential for high-potency inhibin antagonism in gonadotropes. Mol Endocrinol 23:1033-42 |
| Cheng, Edith Y; Hunt, Patricia A; Naluai-Cecchini, Theresa A et al. (2009) Meiotic recombination in human oocytes. PLoS Genet 5:e1000661 |
| Ciarmela, Pasquapina; Wiater, Ezra; Smith, Sean M et al. (2009) Presence, actions, and regulation of myostatin in rat uterus and myometrial cells. Endocrinology 150:906-14 |
| Blount, Amy L; Vaughan, Joan M; Vale, Wylie W et al. (2008) A Smad-binding element in intron 1 participates in activin-dependent regulation of the follistatin gene. J Biol Chem 283:7016-26 |
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