Alzheimer’s Disease (AD):  Kalirin-7 is a protein of 1,663 amino acids, which is predominantly expressed in the adult brain and plays crucial roles in growth and maintenance of neurons.  Our group has discovered that Kalirin-7 mRNA and protein are under-expressed in the hippocampus specimens from 19 AD (Alzheimer’s disease) patients compared to the specimens from 15 controls. In addition, we have found that Kalirin-7 associates with iNOS in the hippocampus, and therefore, Kalirin-7 is complexed with iNOS less in AD hippocampus than in control hippocampus.  In cultured cells, Kalirin-7 associates with iNOS and down-regulates the enzyme activity.

Remarkably, the iNOS (inducible NO synthase) activity is considerably higher in the hippocampus specimens from AD patients than the specimens from controls.  Our study suggests that the under-expression of Kalirin in AD hippocampus contributes to the increased production of deleterious NO in AD brain, further damaging the AD brain.  In addition, we demonstrate that the highly conserved 33 amino acid sequence, K617-H649, of the >1,660 amino acid Kalirin is responsible for the iNOS suppression and that the short peptide mimic corresponding to the K617-H649 sequence down-regulates the iNOS activity in cultured cells.  Our results may provide a novel approach to the AD therapeutics.

Signal Generation by Receptors:  It is generally thought that, to activate a receptor molecule, it has to bind hormone and the hormone-bound receptor or receptor complex activates itself (cis-activation).  In contrast to this cis-activation, there is the emerging evidence that a free (nonliganded) receptor molecule can be activated by another receptor molecule that is complexed with hormone (trans-activation). Trans-activation is difficult to test, because it has to be differentiated from cis-activation and signal generation needs to be distinguished from hormone binding.  We have established a large library of two groups of mutant receptors (>1,000), one deficient in hormone binding and the other deficient in signal generation.  Co-expression of a binding-deficient mutant and a signal-deficient mutant in a cell rescues signal generation, which has established trans-activation.   What was surprising was that trans-activation and cis-activation generate different hormone signals.  Our studies provide a novel approach to inducing a specific hormone signal without invoking other signals associated with the hormone.

Postdoctoral Positions
Postdoctoral scientists to study the gene profiles of Alzheimer's Disease Brains:  We are analyzing Alzheimer's Disease Brains and control human brains to establish a comprehensive AD gene data bank. Toward that end we are seeking postdoctoral fellows, including a woman postdoctoral fellow or one from an under-represented group. Salaries are competitive and facilities are excellent, and the position is open immediately.

Please forward an application letter, a list of three references and CV to Professor Tae H. Ji (tji@uky.edu;  Fax 859-257-3229; Tel 859-257-3163; Department of Chemistry, University of Kentucky, Lexington, KY 40506-0055).

• Youn H, JI I, Ji H, Markesbery WR, Ji TH.  (2007). Under-expression of Kalirin-7 increases iNOS activity in cultured cells and correlates to elevated iNOS activity in Alzheimer’s disease hippocampus.  Journal of Alzheimer’s Disease 12: 271-281
• Youn H, Jeoung M, Koo Y, Ji H, Markesbery WR, Ji I, Ji TH. (2007). Kalirin is under-expressed in Alzheimer’s Disease Hippocampus.  J Alzheimer’s Disease 11: 385-397.
• Jeoung M, Lee C, Ji I, Ji TH. (2007). Trans-activation, Cis-activation and Signal Selection of Gonadotropin Receptors. Mol Cell Endo. 260-262: 137-143.
• Hone E, Martins Ji I, Jeoung M, Ji TH, Grandy SE, Martins RN.  (2005). Alzheimer's disease amyloid-beta peptide modulates apolipoprotein E isoforms specific receptor binding.  J Alzheimers Dis 7:303-14.
• Youn H, Koo Y, Ji I, Ji TH.  (2005). An upstream initiator-like element suppresses transcription of the rat luteinizing hormone receptor gene.  Mol. Endocrinology 19: 1318-1328
• Lee C, Ji I, Ji TH. (2004). Distinct Mechanisms of cAMP Induction by Constitutively activating LH receptor and wild type LH receptor activated by hCG. Endocrine 25: 111-116.
• Ji I, Lee C, Jeoung M, Koo Y, Sievert GA, Ji TH.  (2004). Trans-activation of mutant FSH receptors selectively generates only one of two hormone signals. Mol Endocrinology 18: 968-978.
• Sohn J, Youn H, Jeoung M, Koo Y, Yi C, Ji I and Ji TH. (2003). Orientation of FSH Subunits complexed with the FSH Receptor: b subunit toward the N-terminus of exodomain and a subunit to exoloop 3.  J Biol Chem 278: 47868-76
• Grieshaber NA, Ko C, Grieshaber S, Ji I, Ji TH. (2003). FSH-responsive cytoskeletal genes in rat granulosa cells: Class I b-tubulin, tropomyosin-4 and kinesin heavy chain.  Endocrinology 144:29-39
• Ko C, Grieshaber NA, Ji I, Ji TH. (2003). Follicle stimulating hormone suppresses cytosolic T3-binding protein messenger ribonucleic acid expression in rat granulosa cells.  Endocrinology 144: 2360-2367
• Ji, TH, Ji I.  (2003). Effectors. In Encyclopedia of Hormones: Conn PM, ed.  Academic Press, San Diego PP 475-484.
• Leaños-Miranda A, Aguirre AU, Ji TH, Janovick JA, Conn PM. (2003). Dominant-Negative Action of Disease-Causing GnRHR-Mutants Co-evolved With Decreased Plasma Membrane Expression of GnRHR in Humans. J Clin Endo Metab. 88: 3360-3367.
• Sohn J, Ryu K, Sievert G, Jeoung M, Ji I, Ji, TH. (2002). Follicle Stimulating Hormone interacts with Exoloop 3 of the Receptor.  Biol Chem 277: 50165-75
• Lee CW, Ryu KS, Song YS, Conn PM, Ji I, Ji TH. (2002). Two Defective Heterozygous Luteinizing Hormone Receptors Can Rescue Hormone Action.  J Biol Chem 277: 15795-15800.
• Ji I, Lee CW, Song YS, Conn PM, Ji TH. (2002). Cis- and trans-activation of hormone receptors: the luteinizing hormone receptor. Mol Endocrinology 16: 1299-308
• Castro-Fernandez C, Janovick JA, Brothers S, Fisher RA, Ji TH, Conn PM. (2002). Regulation of RGS3 and RGS10 palmitoylation by gonadotropin-releasing hormone.  Endocrinology 143: 1310-1317.
• Ji TH, Lee CW, Ji I. (2002). Use of defined-function mutants to access receptor-receptor interactions.  Methods 27: 318-323
• Yi CS, Song YS, Ryu KS, Sohn J, Ji, I, Ji TH. (2002). Common and differential mechanisms of gonadotropin receptors. Cell. Mol. Life Sciences 59: 932-940.
• Song YS, Lee HP, Ji I, Ji TH. (2002). Human choriogonadotropin. Wiley Encyclopedia of Molecular Medicine 5: 764-768
• Song YS, Ryu KS, Yi, JS, Ji I, Ji TH. (2002). Luteinizing hormone/choriogonadotropin receptor. Wiley Encyclopedia of Molecular Medicine 5: 1965-1970
• Song YS, Lee CW, Ji I, Ji TH. (2002). Luteinizing Hormone. Wiley Encyclopedia of Molecular Medicine 5: 764-7681962-1965
• Song YS, Yi CS, Ryu KS, Lee CW, Jeoung MK, JiI, Ji TH. (2002). Interaction and Activation of the LH receptor. Indian J Exp Biol. 40: 424-433
• SongYS, JiI, BeauchampJ, Isaacs NW, Ji TH. (2001). Hormone Interactions to Leucine Rich Repeats in the Gonadotropin Receptors:  I.  Analysis of Leu Rich Repeats of Human Luteinizing Hormone/Chorionic Gonadotropin Receptor and Follicle Stimulating Hormone Receptor, J Biol Chem 276: 3426-3435
• SongYS, JiI, BeauchampJ, Isaacs NW, Ji TH. (2001). Hormone Interactions to Leucine Rich Repeats in the Gonadotropin Receptors:  II. Analysis of Leu Rich Repeat 4 of Human Luteinizing Hormone/Chorionic Gonadotropin Receptor, J Biol Chem 276: 3436-3442
• Jeoung MK, Phang T, SongYS, JiI, Ji TH. (2001). Hormone Interactions to Leucine Rich Repeats in the Gonadotropin Receptors:  III. Photoaffinity Labeling of the hCG ab Subunits with the Leucine Rich Repeat 4 Peptide Mimic, J Biol Chem 276: 3443-3450
• Zeng H, Phang T, Song YS, Ji I, Ji TH. (2001). The role of the hinge region in the luteinizing hormone receptor in hormone interaction and signal generation. J Biol Chem 276: 3451-3458
• Grieshaber N, Boitano S, Ji I, Mather JP, Ji TH. (2000). Differentiation of granulosa cell line: FSH induces formation of lamellipodia and filopodia via the adenylyl cyclase/cAMP signal, Endocrinology 141: 3461