Work supported by this grant has concentrated on the neurohypophysis: normal function, primary pathophysiology, and secondary pathophysiology produced by other disorders. We have developed laboratory methods of assessing neurohypophyseal function and have utilized animal models (rats) to study the pathophysiology and metabolic consequences of abnormal function. Complete diabetes insipidus is well understood, but partial loss of function is more common and less well understood. This grant utilizes new methods of solution hybridization to simultaneously quantitate mRNA of vasopressin and oxytocin, and newly developed in vivo measures of translation which will measure rate of biosynthesis and provide an index of time to process precursors. New measures of in vivo transport similarly allow quantitation of hormone transported as well as transport velocity. Each of these individual responses to accelerated hormone transported as well as transport velocity. Each of these individual responses to accelerated hormone release will be evaluated after damage to the neurohypophysis acutely and chronically to determine the mechanism of recovery. The potential for chronic morbidity after partial destruction of the neurohypophysis will be investigated by studying the risk of """"""""recovered"""""""" animals to develop the syndrome of inappropriate antidiuresis with hyponatremia or develop diabetes insipidus when the neurohypophysis is stressed. In another model where the neurohypophysis undergoes acute and then chronic accelerated release of neurohypophyseal hormones and subsequent recovery, the mechanism of the response will be determined by the sequence of changes in message levels, translation, and transport. Changes in hormone synthesis, transport and release in the neurohypophysis will also be investigated in an animal model of chronic suppression of AVP by administration of a potent vasopressin analogue, DDAVP. Lack of down-regulation is a proposed mechanism to explain the high incidence of hyponatremia as a clinical syndrome. Immunohistologic techniques and in situ hybridization will be employed to directly identify the neurons which are involved in recovery from damage, whether new neurons are recruited and/or whether new innervation develops on the original neurons and whether the original neurons change their size and shape in response to need for increased secretion. The studies in lesioned rats are directly attributable to human dysfunction. Ongoing clinical research projects which are relevant to our understanding of the pathophysiology of the neurohypophysis and which undoubtedly respond to stress by the same mechanisms investigated in this grant will be continued. The grant brings new tools of molecular biology to the investigation of problems of immediate clinical relevance and will increase our understanding of the response of the neurohypophysis to injury, to accelerated hormone release, and to inhibition of hormone release.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK016166-14A1
Application #
3225538
Study Section
Endocrinology Study Section (END)
Project Start
1977-01-01
Project End
1990-12-31
Budget Start
1988-01-01
Budget End
1988-12-31
Support Year
14
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Fitzsimmons, M D; Roberts, M M; Robinson, A G (1994) Control of posterior pituitary vasopressin content: implications for the regulation of the vasopressin gene. Endocrinology 134:1874-8
Lee, W S; Abbud, R; Hoffman, G E et al. (1993) Effects of N-methyl-D-aspartate receptor activation on cFos expression in luteinizing hormone-releasing hormone neurons in female rats. Endocrinology 133:2248-54
Roberts, M M; Robinson, A G; Fitzsimmons, M D et al. (1993) c-fos expression in vasopressin and oxytocin neurons reveals functional heterogeneity within magnocellular neurons. Neuroendocrinology 57:388-400
Fitzsimmons, M D; Roberts, M M; Sherman, T G et al. (1992) Models of neurohypophyseal homeostasis. Am J Physiol 262:R1121-30
Mitrakou, A; Vuorinen-Markkola, H; Raptis, G et al. (1992) Simultaneous assessment of insulin secretion and insulin sensitivity using a hyperglycemia clamp. J Clin Endocrinol Metab 75:379-82
Dohanics, J; Hoffman, G E; Verbalis, J G (1991) Hyponatremia-induced inhibition of magnocellular neurons causes stressor-selective impairment of stimulated adrenocorticotropin secretion in rats. Endocrinology 128:331-40
Lee, W S; Smith, M S; Hoffman, G E (1990) Progesterone enhances the surge of luteinizing hormone by increasing the activation of luteinizing hormone-releasing hormone neurons. Endocrinology 127:2604-6
Hoffman, G E; Lee, W S; Attardi, B et al. (1990) Luteinizing hormone-releasing hormone neurons express c-fos antigen after steroid activation. Endocrinology 126:1736-41
Robinson, A G; Roberts, M M; Evron, W A et al. (1989) Total translation of vasopressin and oxytocin in neurohypophysis of rats. Am J Physiol 257:R109-17