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Follistatin biology

In its broadest mission, our research provides fundamental knowledge for the innovation of immunoassays and related methods to precisely distinguish and quantify physiological markers in clinical specimens. These activities serve as a critical link between the basic and clinical investigators. Access to well-validated and standardized assays provides basic studies interpretive power from the large normative and pathophysiologic databases that serve as a crucial backdrop for clinical investigations. Clinical investigations also benefit by our ability to expedite the transfer of basic findings into novel assays that meet the clinical need for innovation, high volume, precise, and sensitive measurements. As clinical investigations increasingly focus upon the genetic basis of human disease, our research activities represents an effective mechanism for providing the requisite analytic methods to characterize phenotypic correlates and to assess the incidence of specific genetic-based defects.

A particular focus over the past 10 years has been the activin-binding protein follistatin. Follistatin is a protein essential for life; loss of function mutants die shortly after birth. Follistatin was discovered in ovarian follicular fluid as an inhibitor of pituitary FSH secretion. However, it is now abundantly clear that the neutralization of activin bioactivity by follistatin(s) is the basis of a widespread autocrine/paracrine system that plays a major role in organogensis during development and organ remodeling in adulthood. Despite the critical importance of follistatin's neutralization of activin, the structural basis of activin binding to follistatin is poorly understood.

Our recent studies have focused upon identifying the specific epitopes directly involved with activin binding and to delineate allosteric effects of activin binding in altering domain-specific antigenic epitopes in the holoprotein. We designed synthetic peptide mimotopes based on the 288 amino acid sequence common to all isoforms of follistatin as direct probes to identify binding epitopes for activin A. In additional to contributions of this project toward understanding how the unique structure of this protein relates to its complex functioning, the knowledge gained has lead to the development of two highly specific immunoassays for the measurement of follistatins. This work has demonstrated that ovarian follicles are not the source of over 95% of peripheral follistatin and that while follistatin plays a critical regulatory role within tissues, such as the prostate, it's role in peripheral blood is unlikely to be regulatory in nature.

In addition to basic investigations to delineate the biochemistry, physiology and pathophysiology of follistatin, our current studies include developing methods and technological approaches for serum measurements of novel ovarian cancer markers. These studies are based upon using only trace amounts of protein targets identified by SELDI and other high resolution screening procedures. The research is directed toward identifying patients with tumors at very early stages and sub-classifying tumor patients according to tumor type or potential responsiveness to therapy.

Finally as Associate Director of the hospital's clinical chemistry laboratories in the Department of Pathology, I conduct studies of current and new clinical methods to evaluate their analytical performance and clinical utility. In this regard, our studies encompass immunoassays for not only endocrine hormones and related analytes but also tumor markers, cardiac markers and therapeutic drugs.

Refereces:

1. Wang QF, Keutmann HT, Schneyer AL, Sluss PM. Analysis of human follistatin structure: Identification of two discontinuous N-terminal sequences coding for activin-A binding and structural consequences of activin binding to native proteins. Endocrinol. 141:3183-3193, 2000.

2. Sidis Y, Schneyer AL, Sluss PM, Johnson LN, Keutmann HT. Follistatin: essential role for the N-terminal domain in activin binding and neutralization. J Biol Chem. 276:17718-26, 2001.

3. Layman L C, Porto ALA,, Xie J, da Motta LAC, da Motta LDC, Weiser W, Sluss PM. FSH beta mutations in a female with partial breast development and a male sibling with normal puberty and azoospermia. J Clin Endo Metab, 87:3702-3707, 2002

4. Klein NA, Harper AJ, Houmard BS, Sluss PM, Soules MR. Is the short follicular phase in older women secondary to advanced or accelerated dominant follicle development? J Clin Endo Metab., 87:5746-50, 2002.

5. Laurich VM, Trbovich AM, O'Neill FH, Houk CP, Sluss PM, Payne AH, Donahoe PK, Teixeira J. Mullerian inhibiting substance blocks the PKA-induced expression of cyctochrome P450 17 alpha-hydroxylase/C 17-20 lyase mRNA in a mouse Leydig cell line independent of CREB phosphorylation. Endocrinology 143:3351-3360, 2002.

6. Kratz A, Lewandrowski KB, Siegel AJ, Sluss PM, Chun KY, Flood JG, Lee-Lewandrowski E. Effect of marathon running on total and free serum prostate-specific antigen concentrations. Arch Pathol Lab Med 127(3):345-34, 2003.

7. Cramer DW, Sluss PM, Powers RD, McShane P, Ginsburg ES, Hornstein MD, Vitonis AF, Barbieri RL Serum prolactin and TSH in an in vitro fertilization population: is there a link between fertilization and thyroid function? J Assist Reprod Genet 20:210-215, 2003.

8. Houmard BS, Hansen KA, Woodruff TK, Sluss PM, Bremner WJ, Soules MR, Klein NA Age-related analysis of inhibin A and B relative to the intercycle monotropic FSH rise in normal ovulatory women. Ann Endocrinol (Paris) 64:86, 2003.

9. Rexrode KM, Manson JE, Lee I-M, Ridker PM, Sluss PM, Cook NR, Buring JE. Sex steroid hormone levels and risk of cardiovascular events in postmenopausal women. Circulation 108:1688-1693, 2003

10. Jain T, Klein NA, Lee DM, Sluss PM, Soules MR. Endocrine assessment of relative reproductive age in normal eumenorrheic younger and older women across multiple cycles. Human Reproduction, 2003

11. Sluss PM, Lee-Lewandrowski E, Flood JS, Eichbaum Q, Lewandrowski K. Establishment of a central laboratory serum tumor marker service on a consolidated immunodiagnostics platform: Development of practice standards, service improvement and operational efficiency. CLMR, IN Press, 2004.

12. Dighe AS, Hayes FJ, Khosravi J, Bodani U, Sluss PM. Comparison of Inhibin A Immunoassays: Recommendation for Adoption of Standardized Reporting. Clin Chem., In Press, 2004

13. Dighe AS, Sluss PM. Improved Detection of Serum Estradiol Following Sample Extraction. Clin Chem., In Press, 2004


	Patrick M. Sluss, Ph.D Follistatin biology In its broadest mission, our research provides fundamental knowledge for the innovation of immunoassays and related methods to precisely distinguish and quantify physiological markers in clinical specimens. These activities serve as a critical link between the basic and clinical investigators. Access to well-validated and standardized assays provides basic studies interpretive power from the large normative and pathophysiologic databases that serve as a crucial backdrop for clinical investigations. Clinical investigations also benefit by our ability to expedite the transfer of basic findings into novel assays that meet the clinical need for innovation, high volume, precise, and sensitive measurements. As clinical investigations increasingly focus upon the genetic basis of human disease, our research activities represents an effective mechanism for providing the requisite analytic methods to characterize phenotypic correlates and to assess the incidence of specific genetic-based defects. A particular focus over the past 10 years has been the activin-binding protein follistatin. Follistatin is a protein essential for life; loss of function mutants die shortly after birth. Follistatin was discovered in ovarian follicular fluid as an inhibitor of pituitary FSH secretion. However, it is now abundantly clear that the neutralization of activin bioactivity by follistatin(s) is the basis of a widespread autocrine/paracrine system that plays a major role in organogensis during development and organ remodeling in adulthood. Despite the critical importance of follistatin's neutralization of activin, the structural basis of activin binding to follistatin is poorly understood. Our recent studies have focused upon identifying the specific epitopes directly involved with activin binding and to delineate allosteric effects of activin binding in altering domain-specific antigenic epitopes in the holoprotein. We designed synthetic peptide mimotopes based on the 288 amino acid sequence common to all isoforms of follistatin as direct probes to identify binding epitopes for activin A. In additional to contributions of this project toward understanding how the unique structure of this protein relates to its complex functioning, the knowledge gained has lead to the development of two highly specific immunoassays for the measurement of follistatins. This work has demonstrated that ovarian follicles are not the source of over 95% of peripheral follistatin and that while follistatin plays a critical regulatory role within tissues, such as the prostate, it's role in peripheral blood is unlikely to be regulatory in nature. In addition to basic investigations to delineate the biochemistry, physiology and pathophysiology of follistatin, our current studies include developing methods and technological approaches for serum measurements of novel ovarian cancer markers. These studies are based upon using only trace amounts of protein targets identified by SELDI and other high resolution screening procedures. The research is directed toward identifying patients with tumors at very early stages and sub-classifying tumor patients according to tumor type or potential responsiveness to therapy. Finally as Associate Director of the hospital's clinical chemistry laboratories in the Department of Pathology, I conduct studies of current and new clinical methods to evaluate their analytical performance and clinical utility. In this regard, our studies encompass immunoassays for not only endocrine hormones and related analytes but also tumor markers, cardiac markers and therapeutic drugs. Refereces: 1. Wang QF, Keutmann HT, Schneyer AL, Sluss PM. Analysis of human follistatin structure: Identification of two discontinuous N-terminal sequences coding for activin-A binding and structural consequences of activin binding to native proteins. Endocrinol. 141:3183-3193, 2000. 2. Sidis Y, Schneyer AL, Sluss PM, Johnson LN, Keutmann HT. Follistatin: essential role for the N-terminal domain in activin binding and neutralization. J Biol Chem. 276:17718-26, 2001. 3. Layman L C, Porto ALA,, Xie J, da Motta LAC, da Motta LDC, Weiser W, Sluss PM. FSH beta mutations in a female with partial breast development and a male sibling with normal puberty and azoospermia. J Clin Endo Metab, 87:3702-3707, 2002 4. Klein NA, Harper AJ, Houmard BS, Sluss PM, Soules MR. Is the short follicular phase in older women secondary to advanced or accelerated dominant follicle development? J Clin Endo Metab., 87:5746-50, 2002. 5. Laurich VM, Trbovich AM, O'Neill FH, Houk CP, Sluss PM, Payne AH, Donahoe PK, Teixeira J. Mullerian inhibiting substance blocks the PKA-induced expression of cyctochrome P450 17 alpha-hydroxylase/C 17-20 lyase mRNA in a mouse Leydig cell line independent of CREB phosphorylation. Endocrinology 143:3351-3360, 2002. 6. Kratz A, Lewandrowski KB, Siegel AJ, Sluss PM, Chun KY, Flood JG, Lee-Lewandrowski E. Effect of marathon running on total and free serum prostate-specific antigen concentrations. Arch Pathol Lab Med 127(3):345-34, 2003. 7. Cramer DW, Sluss PM, Powers RD, McShane P, Ginsburg ES, Hornstein MD, Vitonis AF, Barbieri RL Serum prolactin and TSH in an in vitro fertilization population: is there a link between fertilization and thyroid function? J Assist Reprod Genet 20:210-215, 2003. 8. Houmard BS, Hansen KA, Woodruff TK, Sluss PM, Bremner WJ, Soules MR, Klein NA Age-related analysis of inhibin A and B relative to the intercycle monotropic FSH rise in normal ovulatory women. Ann Endocrinol (Paris) 64:86, 2003. 9. Rexrode KM, Manson JE, Lee I-M, Ridker PM, Sluss PM, Cook NR, Buring JE. Sex steroid hormone levels and risk of cardiovascular events in postmenopausal women. Circulation 108:1688-1693, 2003 10. Jain T, Klein NA, Lee DM, Sluss PM, Soules MR. Endocrine assessment of relative reproductive age in normal eumenorrheic younger and older women across multiple cycles. Human Reproduction, 2003 11. Sluss PM, Lee-Lewandrowski E, Flood JS, Eichbaum Q, Lewandrowski K. Establishment of a central laboratory serum tumor marker service on a consolidated immunodiagnostics platform: Development of practice standards, service improvement and operational efficiency. CLMR, IN Press, 2004. 12. Dighe AS, Hayes FJ, Khosravi J, Bodani U, Sluss PM. Comparison of Inhibin A Immunoassays: Recommendation for Adoption of Standardized Reporting. Clin Chem., In Press, 2004 13. Dighe AS, Sluss PM. Improved Detection of Serum Estradiol Following Sample Extraction. Clin Chem., In Press, 2004