Estrogen has multiple salutary neuromodulatory, neurotrophic, and neuroprotective properties.  These salutary effects are presumably mediated through the estrogen receptors that are widely, but selectively distributed throughout the brain.  In particular, estrogen receptors are densely populated in the neocortex, hippocampus, amygdala, and basal forebrain; areas of the brain that are afflicted by Alzheimer's disease (AD) and underlie specific cognitive functions impaired in patients with AD.  Moreover, these cognition-mediating regions of the brain demonstrate neurotrophic activity in response to estrogen release.  Preliminary evidence from clinical studies indicates that administration of estrogen improves memory in postmenopausal women with AD.  In addition, results of epidemiological studies suggest that estrogen therapy might reduce the risk of developing AD.  However, several issues of critical clinical significance need to be further evaluated before the potential role of estrogen for the treatment of AD can be firmly established.  These issues include the following:  1) whether the cognition-enhancing actions of estrogen are dose-dependent and persist over an extended period of administration,  2) if the salutary effects of estrogen on cognitive function will effectively translate into improved skills of independent living, 3) whether the potential beneficial effects on cognition and physical function will persist when estrogen is co-administed with a progestin over both short and extended periods, and finally, 4) whether ApoE genotype influences the therapeutic response of an individual to treatment with estrogen.  The proposed randomzied, double-blind, placebo-controlled, parallel-group design clinical study will evaluate the dose-dependent effects of prolonged administration of both unopposed and opposed (i.e., with a progestin) estrogen on cognitive function and skills of independent living in postmenopausal women with AD.  

A desirable outcome of health care of geriatric patients is continued independent functioning even in the presence of disease. Little is known about the impact of primary care provider practice on functional status in the elderly.  The proposed study thus seeks to examine the relationship between generalist provider practice and clinically important functional status changes in community-dwelling elderly.  The main outcome of interest will be clinically significant functional decline over a four year period.  We hypothesize that a "geriatric-focused" approach to the elder patient - specifically, prescribing medications according to geriatric principles, screening for geriatric syndromes, and involving allied health care professionals (mental health, nutrition, physical therapy, social work) in the management of the older patient will be associated with less patient functional decline.  Data from a prospective cohort study will provide the patient-level data for this study; automated data will be used to obtain provider-level data.  Subjects will be a subset of the cohort who are independent in basic activities of daily living (ADL's), have high self-assessed health status, and are free of dementia.  Patient factors which will be controlled for in multiple regression models include demographic factors (age, gender, race), comorbid conditions (congestive heart failure, depression, cognitive impairment, visual impairment, hypertension, stroke, arthritis, diabetes), behavioral factors (low physical activity, infrequent social contacts, alcohol and tobacco use), physiologic factors (body mass index, lower extremity strength), and duration with provider.  The findings of this analysis will direct future studies that test the efficacy of provider-based interventions in preventing functional decline in elderly adults. 

Two diseases of prostate epithelium, benign prostatic hyperplasia (BPH) and prostate cancer, are among the major health problems faced by American men.  Deregulation of prostatic epithelial cell proliferation is a central event in both benign and malignant prostatic disease.  The objective of this proposal is to understand the role(s) of two tyrosine kinase growth factor families, their ligands and associated binding proteins, and the androgen receptor in control of prostatic epithelial cell mitogenesis and differentiation.  We will use a well characterized family of SV40-T antigen-immortalized human prostate epithelial cells (PEC).  As well as primary cultures of human prostatic epithelial cells, obtained from surgical specimens, to achieve the following specific aims:  1) to proliferation of SV40-T immortalized human PEC lines.  Growth factor responses will be studied individually and in combination for impact on cell growth and receptor mediated signal transduction.  Functional significance will be tested by study of the effect of disruption of growth factor receptor function; 2) to construct androgen receptor positive sublines of these immortalized cell lines by transfection of a full length androgen receptor into these cells, to permit study of the impact of EGF and IGF on these cells in the presence and absence of androgens; 3) to construct new SV40-T antigen immortalized human PEC lines by transfection with a construct o the SV40T antigen gene controlled by an inducible promotor.  This will permit study of growth factor effects in the absence or presence of SV40T antigen; and 4) to test the capacity of these cells for proliferation and/or differentiation within the prostate of the athymic nude mouse.  Investigation of the EGFr, IGFr, and androgen receptor systems as interactive networks is essential for development of effective new treatments for abnormal prostatic growth.

Regulation of Fat and Muscle Mass by Interleukin-15
USDA National Research Initiative Cooperative State Research, Education, and Extension Service
December 1, 2004 - November 31, 2008
LeBris S Quinn PhD

This study seeks to determine the role of muscle-derived IL-15 in determining fat:lean body composition in developing animals, investigate the control of IL-15 expression in muscle tissue, and determine if IL-15 directly inhibits TNF-α signaling in muscle and adipose cell cultures.

IL-15, Body Composition and Insulin Sensitivity in Aging

NIH/National Institute on Aging
March 15, 2006 - December 31, 2010
LeBris S Quinn PhD

The goals of this project are to characterize changes in the IL-15 system during aging, and determine if transgenic mice which over express IL-15 in muscle will exhibit resistance to age-associated loss of skeletal muscle, increased insulin resistance, and increases in fat deposition.

Wound healing is impaired in aging with consequent delay in closure and increased risk for dehiscence and infection.  This age-associated impairment in wound repair is due, in part, to delayed neovascularization.   The successful growth of new blood vessels requires coordinated cellular functions including migration, proliferation, and biosynthesis/breakdown of matrix proteins.   Although each of these processes may be impaired in aging, our preliminary data show that decreased migration of micovascular endothelial cells contributes to delayed angiogenesis.  The long-term objective of this proposal is to define the mechanism(s) of impaired migration in aged endothelial cells and, thus, identify potential sites for interventions to improve wound healing in aging.

In vitro, migration of aged human microvascular endothelial cells (hmEC) is slowed on collagen I, the major extracellualr matrix (ECM) protein present during the angiogenic phase of wound repair.  Optimal migration of cells requires the dynamic breaking and forming of cell-matrix contacts.  Thus, movement is regulated by matrix degrading proteases (such as interstitial collagenase-matrix metalloprotease I, MMP1), integrins (such as alpha2 beta1, which induces MMP1 upon binding to collagen I), and their interaction with ECM.  Aged hmEC express less MMP1 and secrete increased amounts of tissue inhibitor of metalloprotease 1 (TIMP1) relative to young hmEC.  Moreover, in vivo, delayed neovascularization of polyvinyl alcohol sponges in aged mice is associated with decreased MMP1 and increased TIMP1 expression.  Stimulation of aged hmEC with vascular endothelial growth factor (VEGF) increases their movement, an effect which may result from induction of MMP1.

The hypothesis of this application is that aged hmEC have impaired migration due to decreased synthesis of MMP1.  We propose that alpha2 beta1-collagen I binding does not properly function to induce MMP1 synthesis which is necessary for selective detachment during migration.  Moreover, as MMP1 is required to generate ligation sites for alpha 2 beta1, selective attachment cannot occur in a coordinated fashion.  Using young hmEC and young mice as controls, the following Specific Aims are proposed: 1. Elucidate the role of MMPI/TIMP in the impaired migration of aged hmEC on collagen I; 2. Define the expression and function of alpha2 beta1, and its interaction with MMP1, in impaired attachment and migration of aged hmEC; 3.  Identify the mechanism by which VEGF enhances the migration of aged hmEC; and 4.  Determine the effects of age and VEGF on:  expression and function of MMP1/TIMP1 and alpha2 beta1, and the migration of micovascular EC during angiogenesis in vivo.

Angiogenesis is delayed in aging. The delay in blood vessel formation is detrimental to the formation of capillaries in ischemic tissue. While the reasons for impaired neovascularization in aging are multifactorial, our data show that delayed migration of endothelial cells contributes to impaired neovascularization. Little is known about the changes in cellular migration which occur with age. We have found that aged human microvascular endothelial cells (hmEC) secrete high levels of the matrix metalloprotease MMP2 relative to young cells. Our proposal will examine the hypothesis that dysregulation of protease synthesis and inhibition results in the delay in migration of aged hmEC in 3 dimensional collagen, a substrate akin to that which is present during angiogenesis in vivo. We will use vascular endothelial cell growth factor (VEGF) to examine how this growth factor, which enhances cellular migration in aging on 2D collagen but not within 3 D collagen, modulates the expression of MMPs. The elucidation of the mechanisms behind delayed migration in aged microvascular endothelium has implications for the modulation of neovascularization in aging.

Weight loss in geriatric patients is a common and worrisome problem. The etiology of lack of appetite in the face of continued weight loss is unknown. Previous studies have shown an increase in mortality rates, frailty, and functional disability among older persons with involuntary weight loss. The long-term objective of this research is to determine the underlying pathophysiology of involuntary weight loss and anorexia in the geriatric population. One previous study has reported possible dysregulation of energy intake in older men after calorie restriction. Other studies have suggested abnormalities in leptin homeostasis in older adults. Therefore, the specific aims of the proposed project are to determine whether a period of moderate caloric restriction suppresses integrated diurnal plasma leptin levels (AUC-leptin) and resting energy expenditure (REE) in healthy older subjects to the same degree as in young adults, and to determine whether the compensatory increase in energy intake following a period of dietary energy restriction is as robust in older subjects as it is in young adults. A cross-sectional comparison of healthy community dwelling older and younger adults before and after calorie restriction will be performed. After 2 weeks on a weight-maintaining diet, subjects will have hourly blood specimens drawn for 24 hours for leptin and insulin determination. Fasting blood specimens for pro-inflammatory cytokines and hormones known to be associated with energy regulation and metabolism will be obtained, and REE will be measured. A DEXA scan and a three slice abdominal CT scan will be performed to measure each subject's total and intraabdominal fat mass. Subjects will then be placed on a 30% calorie reduction diet for 3 weeks. Following this period of energy restriction, subjects will undergo a second diurnal blood sampling protocol and determination of REE, DEXA and CT scans. Subjects will return to an ad libitum diet and daily caloric intake will be measured for the subsequent 2 weeks. The expected compensatory increase in energy intake will be compared in the two subject groups to determine whether this important mechanism for preserving body composition is impaired by aging.