The factors inducing both normal and abnormal prostate growth have been considered to act largely via endocrine mechanisms. Other factors have been implicated in prostate development including growth factors and stromal-epithelial cell interactions. However, until recently, little attention has been paid to the role of the autonomic nervous system (ANS) in prostate growth and differentiation under normal and abnormal conditions. We have recent experimental evidence in an animal model that supports a significant role of the ASN in promoting both prostate hyperplasia and atrophy by the selective manipulation of the parasympathetic (hyperplasia) and sympathetic (atrophy) innervation. This proposal is based upon the hypothesis that the ANS has an important, constant and broad regulatory role on the differentiation and function of the prostate gland. The experiments detailed below are designed to make known both the existence of and the mechanism(s) by which this novel neuroregulation influences prostate growth using a model developed in our lab. This research design is structured to test the overall hypothesis that perturbations of this neural regulatory mechanism lead to an increase in prostate innervation and autonomic hyperactivity in nearby in non-perturbed prostate tissues resulting in increased growth. The perturbation of the prostate innervation by selective neurectomy leads to a gland wide increase in nerve growth factor and possibly other growth factors. This induced NGF increases autonomic hyperinnervation in the un-perturbed prostate tissue resulting in an increase in local neurotransmitter levels by increasing cell division and decreasing prostatic apoptosis. These neural regulatory changes culminate in prostatic hyperplasia.
The Specific Aims to be addressed are: 1) Test the hypothesis that innervation induces prostate wide increases in NGF. 2) Test the hypothesis that neural manipulation induces hyperinnervation in non-perturbed prostate tissue. 3) Test the hypothesis that NGF is responsible for the hyperplasia by direct action on prostate cells or via hyperinnervation using stromal and epithelial cell culture techniques of rat prostates. 4) Test the hypothesis that the hyperplasia of hyperinnervation occurs by an increase of prostate cell proliferation and reduced apoptosis. Using this model allows one to explore the limits of understanding prostatic neuroregulation, to explore neurotrophic influences on exocrine gland development, and to possibly uncover novel methods to influence prostate disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054478-04
Application #
6381240
Study Section
Special Emphasis Panel (ZRG4-UROL (01))
Program Officer
Mullins, Christopher V
Project Start
1998-09-30
Project End
2002-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
4
Fiscal Year
2001
Total Cost
$173,277
Indirect Cost
Name
Northwestern University at Chicago
Department
Urology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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