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Relaxin and Related Peptides: Fifth International Conference, Volume 1160


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Relaxin is a protein hormone, produced and secreted during pregnancy in mammalian species, having superficial structural features resembling those of insulin. Since its initial isolation from the ovaries of pregnant pigs in 1976, increasing interest in relaxin has led to increased understanding of the chemistry, synthesis, secretion, biological roles, mechanisms of action, and potential clinical applications of relaxin in humans and domestic animals.

In pigs, rats, and mice, relaxin promotes growth and softening of the cervix, enabling rapid and safe delivery of the fetuses. In these species relaxin also promotes growth and development of the mammary apparatus.

Recently, biological effects of relaxin in the heart, kidney, liver, and brain have been identified, and these discoveries have triggered additional interest in possible clinical applications for relaxin. In 2002, a second form of relaxin, which is found primarily in the brain, was discovered.

Relaxin-like factor (also called insulin 3), which was discovered in 1993, is produced in the fetal testis and plays a major role in testicular descent during development. The recent identification of the receptors for both relaxin and relaxin-like factor has enabled more rigorous studies of the target tissues and mechanisms of action of these hormones.

This volume contains a description of recent advances and future research and clinical possibilities in the field of relaxin and related peptides.

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Preface (G. Bryant-Greenwood).

Tribute. Bernard G. Steinetz, Jr.: A Most Tenacious Relaxinologist (O. David Sherwood).

Part I: Relaxin and Related Peptides: Structure and Function.

1. Structure and Activity in the Relaxin Family of Peptides (Geoffrey Tregear et al.).

2. The Chemical Synthesis of Relaxin and Related Peptides: A Historical Perspective (John D. Wade et al.).

3. De Novo Design and Synthesis of Cyclic and Linear Peptides to Mimic the Binding Cassette of Human Relaxin (Mohammed Akhter Hossain et al.).

4. Structural Insights into the Function of Relaxins (K.Johan Rosengren et al.).

5. Structural Properties of Relaxin Chimeras: NMR Characterization of the R3/I5 Relaxin Peptide (Linda Haugaard-Jonsson et al.).

6. Probing the Functional Domains of Relaxin-3 and the Creation of a Selective Antagonist for RXFP3/GPCR135 over Relaxin Receptor RXFP1/LGR7 (Changlu Liu et al.).

7. Degradation of Relaxin Family Peptides by Insulin-Degrading Enzyme (Robert Bennett et al.).

8. The Relationship between Relaxin Family Genes in Humans and Teleosts Revealed Through Bioinformatic Analyses and the Expression of Three RLN Genes in Teleosts Verified (Sergey Yegorov et al.).

Part II: Relaxin Family Receptors.

9. Structural Basis of Allosteric Ligand-Receptor Interactions in the Insulin/Relaxin Peptide Family: Implications for other receptor Tyrosine Kinases and G Protein-Coupled Receptors (Pierre De Meyts et al.).

10. Dimerization and Negative Cooperativity in the Relaxin Family Peptide (RXFP) Receptors (Angel Svendsen et al.).

11. Mechanism of Relaxin Receptor (LGR7/RXFP1) Expression and Function (Andras Kern et al.).

12. Resolving the Unconventional Mechanisms Underlying RXFP1 and RXFP2 Receptor Function (Brigham J. Hartley et al.).

13. Modeling the Primary Hormone Binding Site of RXFP1 and RXFP2 (Daniel Scott et al.).

14. Activation of Relaxin Related Receptors by Short, Linear Peptides Derived from a Collagen Containing Precursor (Ronen Shemesh et al.).

15. Development of Lanthanide-Labeled Human INSL3 as an Alternative Probe to Radioactively-Labeled INSL3 for use in Bioassays (Richard Hughes et al.).

16. Relaxin Receptor LGR7 (RXFP1) is Regulated by Estrogen (Priya Maseelall et al.).

Part III: Relaxin and Related Peptides (Receptor Signaling).

17. The "Hot Wires" of the Relaxin-Like Factor (INSL3) (Christian Schwabe and Erike E. Bullesbach).

18. Roles of the Receptor, the Ligand and the Cell in the Signal Transduction Pathways Utilised by the Relaxin Family Peptide Receptors 1-3 (RXFP1-3) (Roger J Summers et al.).

19. Addition of a Carboxy-Terminal Green Fluorescent Protein (GFP) Does Not Alter the Binding and Signaling Properties of the Relaxin Family peptide Receptor (RXFP3) (Emma Van der Westhuizen et al.).

20. Relaxin Activates Multiple cAMP Signaling Pathway Profiles in Different Target Cells (Michelle Halls et al.).

21. Relaxin Family Peptide Receptor 1 (RXFP1) Activation Stimulates the Peroxisome Proliferator-Activated Receptor Gamma (Sudhir Singh et al.).

22. RXFP1 Couples to the Gai3-Gßγ-P13Cζ Pathway via the Final 10 Amino Acids of the Receptor C-Terminal Tail (Michelle L. Halls et al.).

Part IV: Reproductive Functions of Relaxin and Related Peptides.

23. Relative Roles of the Epithelial and Stromal Tissue Compartment(s) in Mediating the Actions of Relaxin and Estrogen on Cell Proliferation and Apoptosis in the Mouse Lower Reproductive Tract (Lijuan Yao et al.).

24. Relaxin in Human Pregnancy (Laura T Goldsmith and Gerson Weiss).

25. Identification of the Relaxin-Responsive Cells in the Human Choriodecidua at Term (Jaime S. Horton et al.).

26. Relaxin in Endometriosis (Sara S. Morelli et al.).

27. Relaxin Supports Implantation and Early Pregnancy in the Marmoset Monkey (Almuth Einspanier et al.).

28. Expression of LGR7 in the Primate Corpus Luteum Implicates the Corpus Luteum as a Relaxin Target Organ (Priya B. Maselall et al.).

29. Milk-Borne Relaxin and the Lactocrine Hypothesis for Maternal Programming of Neonatal Tissues (Carol A. Bagnell et al.).

30. Relaxin and Maternal Lactocrine Programming of Neonatal Uterine Development (Frank F. Bartol et al.).

31. Biological Activity of Relaxin in Porcine Milk (Amy-Lynn Frankshun et al.).

32. Evaluation of Systemic Relaxin Blood Profiles in Horses as a Means of Assessing Placental Function in High-Risk Pregnancies and Responsiveness to Therapeutic Strategies (Peter L Ryan et al.).

33. Relaxin Concentrations in Serum and Urine of Endangered and Crazy Mixed-up Species: New Methods, Uses and Findings (Bernard Steinetz et al.).

34. Conceptus Numbers Do Not Affect Blood Concentrations of Relaxin in the Rabbit (Phillip Fields and Michael Fields).

35. Perinatal Zearalenone Exposure Affects RXFP1, RXFP2 and Morphoregulatory Gene Expression in the Neonatal Porcine Uterus (Joseph C. Chen et al.).

36. Laser Microdissection of Neonatal Porcine Endometrium for Tissue Specific Evaluation of Relaxin Receptor (RXFP1) Expression in Response to Perinatal Zearalenone Exposure (Anne A. Wiley et al.).

37. RXFP1 Is Expressed on Sperm Acrosome and Relaxin Stimulates the Acrosomal Reaction of Human Spermatozoa (Lisa Gianesello et al.).

38. Identification of Boar Testis as a Source and Target Tissue of Relaxin (Tetsuya Kohsaka et al.).

Part V: Physiology of Insulin-Like Peptide 3.

39. INSL3/RXFP2 Signaling in Testicular Descent: Mice and Men (Shu Feng et al.).

40. Nuclear Receptors, Testosterone and Post-Translational Modifications in Human INSL3 Promoter Activity in Testicular Leydig Cells (Jacques J Tremblay et al.).

41. Mutations in INSL3-RXFP2 Genes in Cryptorchid Boys (Alberto Ferlin et al.).

42. New Roles for INSL3 in Adults: Regulation of Bone Metabolism and Association of RXFP2 Gene Mutations with Osteoporosis (Albero Ferlin et al.).

43. INSL3 Plays a Role in the Balance Between Bone Formation and Resorption (Anastasia Pepe et al.).

44. Role of Relaxin in Human Osteoclastogenesis (Arianna Facciolli et al.).

Part VI: Neurobiology of Relaxin and Relaxin-Related Peptides.

45. Relaxin Family Peptides and Receptors in Mammalian Brain-Anatomical Insights and Diverse Functional Possibilities (Andrew L. Gundlach et al.).

46. Behavioral Phenotyping of Mixed-Background (129S5:B6) Relaxin-3 Knockout Mice (Craig M. Smith et al.).

47. Metabolic and Neuroendocrine Reponses to RXFP3 Modulation in the CNS (Steven W. Sutton et al.).

48. Relaxin-3 and Its Role in Neuroendocrine Function (Barbara M.C. McGowan et al.).

49. Distribution of Relaxin-3 mRNA and Immunoreactivity and RXFP3 Binding Sites in the Brain of the Macaque, Macaca fascicularis (Sherie Ma et al.).

50. Verification of a Relaxin-3 Knockout/LacZ Reporter Mouse as a Model of Relaxin-3 Deficiency (Craig M. Smith et al.).

51. Development and Optimization of mi RNA against Relaxin-3 (Gabrielle E. Callander et al.).

52. An in Vitro Study of the Protective Effect of Relaxin on Brain Tissue under Ischemic Stress (Brian C. Wilson and Rebecca Rappaport).

Part VII: Cardiac Actions of Relaxin.

53. Prominent Role of Relaxin in Improving Post-Infarction Heart Remodelling. Clues from in vivo and in vitro Studies with Genetically Engineered Relaxin-Producing Myoblasts (Daniele Bani et al.).

54. Reversal of Cardiac Fibrosis and Related Dysfunction by Relaxin: Experimental Findings (Xiao-Jun Du et al.).

55. a1-Adrenergic Activation Upregulates Expression of Relaxin Receptor RXFP1 in Cardiomyocytes (Xiao-Lei Moore et al.).

56. Relaxin Promotes Matix Metalloproteinase-2 and Decreases Wnt/ß-Catenin Expression in the Neonatal Porcine Heart (The-Yuan Ho et al.).

Part VIII: Renal and Vascular Actions of Relaxin.

57. Relaxin: An Endogenous Renoprotective Factor? (Tim D. Hewitson and Chrishan S. Samuel).

58. Investigations into the Inhibitory Effects of Relaxin on Renal Myofibroblast Differentiation (Chrishan S. Samuel et al.).

59. Effects of Relaxin on the Development of Mesangial Proliferative Nephritis (Naoki Ikegaya et al.).

60. The Role of Relaxin in Maternal Systemic and Renal Vascular Adaptations During Gestation (Jonathan T. McGuane et al.).

61. Relaxin-Induced Changes in Renal Function and RXFP1 Receptor Expression in the Female Rat (Alsadek H. Bogzil and Nick Ashton).

62. Regulation of Rxfp2 (lgr8) Expression in the Mouse Fetal Kidney by the Transcription Factor Pod1 (Mary Familari et al.).

63. Relaxin as a Protective Substance in the Preserving Solution for Liver Transplantation: Spectrophotometric in vivo Imaging of Local Oxygen Supply in an Isolated Perfused Rat Liver Model (Marcus U. Boehnert et al.).

Part IX: Actions of Relaxin on the Extracellular Matrix.

64. MMP Induction by Relaxin Causes Cartilage Matrix Degradation in Target Synovial Joints: Receptor Profiles Correlate with Matrix Turnover (Sunil Kapila et al.).

65. Relaxin’s Involvement in ECM Homeostasis: Two Diverse Lines of Evidence (Timothy E. Cooney et al.).

66. Scar Prevention and Cosmetically Enhanced Wound Healing Using Relaxin (Dennis R. Stewart).

67. Role of Relaxin in the Regulation of Fibrosis in the Lung (Mimi Tang et al.).

68. Relaxin Reduces Fibrosis in Models of Progressive and Established Hepatic Fibrosis (Robert Bennett et al.).

69. Evaluation of Relaxin’s Antifibrotic Action by Seldi-TOF Mass Spectrometry-Based Profiling of Relaxin KO Mice, a Model of Progressive Fibrosis (Eleni Giannakis et al.).

Part X: Relaxin and Cancer.

70. Relaxin Promotes Clustering, Migration and Activation States of Mononuclear Myelocytic Cells: Implications of Leukocyte Responsiveness to Tumor-Derived Relaxin (Michael Cox et al.).

71. Lysosomal Acid Hydrolases of the Cathepsin Family are Novel Targets of INSL3 in Human Thyroid Carcinoma Cells (Joanna Bialek et al.).

72. Estrogen and TCDD influence RLN2 Gene Activity in Estrogen-Receptor Positive Human Breast Cancer Cells (Silke Kietz et al.).

73. Relaxin Signaling in Uterine Fibroids (Zhen Li et al.).

74. Relaxin/RXFP1 Signaling in Prostate Cancer Progression (Shu Feng et al.).

Part XI: Relaxin Clinical Trials.

75. Scientific Rationale and Design of a Phase I Safety Study of Relaxin in Women with Severe Preeclampsia (Elaine Unemori et al.).

76. A Randomized, Double Blind, Placebo Controlled Trial of Relaxin for Cervical Ripening in Post-Date Pregnancies (Gerson Weiss et al.).

77. First Clinical Experience with Intravenous Recombinant Human Relaxin in Compensated Heart Failure (Thomas Dschietzig et al.).