Per1 regulated SGLT1 expression in the pathogenesis of BPH during aging Benign prostatic hyperplasia (BPH) is characterized by increased amount of cellular elements of the prostate, which may lead to restriction of the flow of urine from the bladder. BPH is one of the most prevalent diseases that affect the life quality o aging men. It is estimated that 50% of men present histopathologic BPH by age of 60 and 90% by age of 85. We recently have found that the expression of the sodium/glucose co-transporter 1(SGLT1) is significantly altered in BPH tissues, i.e., SGLT1 is weakly expressed only in the luminal epithelial cells of normal prostates, but it is significantly up- regulated in the basal cels and stromal cells of BPH tissues. SGLT1 is an active glucose transporter that transports glucose into cells in a [Na+] dependent and [glucose] independent manner. SGLT1 and altered glucose metabolism may play important roles in the pathogenesis of BPH. It has recently been found by others that the expression of SGLT1 is negatively regulated by a circadian gene, Period 1 (Per1). Decrease in Per1 functions is known as a part of aging process, which is linked with aging related symptoms such as altered energy metabolism and hormone homeostasis. Per1 knockout mice present advanced aging phenotypes in peripheral tissues as well, such as the ovary, however, the prostate phenotypes of these mice are yet to be determined. Based on the literatures that Per1 negatively regulates SGLT1 expression;decrease in Per1 functions is a part of aging process, Per1 is involved in energy metabolism;altered energy metabolism is tightly related to the incidence of BPH that is also an aging related disease;and our own recent finding that the expression of SGLT1 is significantly increased in BPH tissues, we hypothesize that decrease in Per1 functions during aging induces SGLT1 expression in the prostate, which play important roles in the pathogenesis of BPH. The following specific aims are designed to address our hypothesis: 1. Determine the prostate phenotype of Per1 knockout mice (commercially available) during aging 2. Determine the role of SGLT1 in basal cell in the pathogenesis of BPH using a basal cell specific inducible SGLT1 transgenic mouse model. 3. Determine the role of SGLT1 in stromal cells on the growth of prostate stromal and epithelial cells in vitro and in vivo The outcomes of this exploratory study will lay down the basement to establish a relationship between aging and prostate glucose metabolism in the pathogenesis of BPH, which bear a potential of offering molecular mechanisms for developing novel approaches targeting at glucose metabolism to prevent and treat BPH.

Public Health Relevance

Per1 regulated SGLT1 expression in the pathogenesis of BPH during aging We recently have found that the expression of the sodium/glucose co-transporter 1(SGLT1) is significantly increased in tissues of benign prostatic hyperplasia (BPH). Others have found that an aging related circadian gene Per1 negatively regulates the expression of SGLT1. This proposal is to determine the roles of Per1 and SGLT1 in the pathogenesis of BPH during aging. The outcomes of this exploratory study will lay down the basement to establish a relationship between prostate glucose metabolism and the pathogenesis of BPH, which bear a potential of offering molecular mechanisms for developing novel approaches targeting at glucose metabolism to prevent and treat BPH.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG045382-01A1
Application #
8698528
Study Section
Special Emphasis Panel (ZRG1-UGPP-G (08))
Program Officer
Murthy, Mahadev
Project Start
2014-08-01
Project End
2016-03-31
Budget Start
2014-08-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$225,750
Indirect Cost
$75,750
Name
University of Houston
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
036837920
City
Houston
State
TX
Country
United States
Zip Code
77204