Sample Executive Summaries

The sample executive summaries are in the three project areas of basic/biomedical research, clinical investigation, and health services research/epidemiology.

Basic/Biomedical Research

The goal of this proposal is to determine the mechanisms by which overexpression of nitric oxide (NO) or its reactive nitrogen species, ONOO, may promote tissue injury (enterocyte apoptosis) and inhibit tissue repair mechanisms (epithelial restitution via enterocyte migration and proliferation), thereby leading to gut barrier failure.  Specific aims are to determine the signaling pathways in ONOO-mediated enterocyte apoptosis, and to examine the mechanisms by which NO or ONOO inhibits tissue repair mechanisms in enterocytes.

The project focuses on the use of surface enhanced laser desorption and ionization in the discovery of new biomarkers for ovarian cancer.  This technology is capable of detecting differences in protein expression in microdissected ovarian cancer tissue.

Ischemic and inflammatory diseases target the vascular endothelium and are characterized by cytokine production and endothelial (EC) barrier dysfunction. Preliminary observations indicate that vascular endothelial cadherin (VE cadherin), a major component of endothelial adherens junctions, is important in EC barrier dysfunction. The overall objective is to determine the relationsip between tumor necrosis factor (TNF) -induced rho and MAPkinase activation and the phosphorylation of VE cadherin, and to relate cadherin phosphorylation to junctional disassembly and EC barrier dysfunction.

Using transgenic rats and adeno-associated viral vectors, the candidate will modulate GAD2 and VGAT gene expression in lateral thalamic nuclei to determine the central mechanisms controlling post-herpetic neuralgia (PHN), a chronic, debilitating pain resulting from shingles.  These methods will dissect contributing factors resulting in women reporting more post-herpetic neuralgia than men. The goal of this research is to address the effect of GABAergic genes on the orofacial nociceptive response during PHN and determine their roles in the gender differences in orofacial PHN pain.

The candidate plans to test the hypothesis that insulin signaling in the reproductive axis is critical for normal fertility. The plan is to determine whether insulin regulates gonadotroph-specific gene expression via pathways that are similar to or distinct from those mediating effects of gonadotropin-releasing hormone on pituitary gene expression. The initial approach will be to determine the role of insulin signaling in the gonadotroph using a conditional knock-out of the insulin receptor in the anterior pituitary.

Respiratory papillomas are benign hyperplastic tumors of respiratory mucosa which cause significant morbidity and mortality, mainly due to obstruction of the airway, and have malignant potential. Human papillomaviruses (HPV), the causative agent of respiratory papillomas, have a life cycle that involves a quiescent or latent infection of squamous epithelial basal cells and transcriptional activation as the basal cell undergoes differentiation toward a mature keratinocyte. The objective of this project is to study how the expression of HPV early genes is regulated during the earliest stages of viral reactivation and how the early genes relate to cellular differentiation.

The goal of this project is to define signaling pathways that regulate transplant arteriopathy.  Smooth muscle cell (SMC) proliferation plays a prominent role in the development of this arteriopathy.  Because previous studies have shown that activation of cAMP-PKA signaling inhibits SMC proliferation, this project focuses on that pathway. cAMP could have direct inhibitory effects on cell growth or could act by inhibiting a growth-stimulatory pathway such as the ras-raf MAP kinase pathway. To distinguish between these, inhibitors of the ras-raf-MAP kinase pathway may also be examined. Evidence gained by such experiments will permit identification of the most effective mechanisms for attenuating transplant arteriopathy first in a mouse aortic transplant model.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by widespread immunologic abnormalities and multi-organ involvement. A consistent manifestation of immune dysfunction in SLE is the hyperactivity of the humoral immune system, both in vitro and in vivo. The hypothesis to be tested is that an ectopic germinal center (GC) reaction occurs in SLE patients. A possible driver of this germinal center reaction is the ectopic expression of CD40-L on SLE B and/or T cells.

Clinical Investigation

Arterial hypertension, a disease that affects over 50 million Americans, is the most common cause of left ventricular hypertrophy. Because recent studies have underscored the negative prognosis of left ventricular hypertrophy as an independent risk factor for cardiac morbidity and mortality, regression of left ventricular hypertrophy with anti -hypertensive medication has become a goal of treatment.  The major goal of this project is to study the relationship of the development of left ventricular hypertrophy with alterations in myocardial metabolism. A second objective is to explore the potential role of genetic variants in the peroxisome-proliferator-activated receptor alpha.

Firearm injuries are a major public health problem, especially among teenagers and young adults. Although the adverse effects of acute and long-term retention of lead in the body are well known, little effort has been made to consider the effects of retention of missiles following gunshot injuries. The goal of this project is to reduce the morbidity associated with an increased body lead burden as a result of retained bullets from firearm injuries.

The candidate proposes to conduct two case-controlled studies to assess the protective efficacy of vaccines as they are used in clinical practice. The vaccines to be studied are two recently licensed — the varicella vaccine and the Lyme disease vaccine. Questions remain with respect to the timing and the effect of vaccination on the severity of disease in patients who contract the disease despite vaccination.

Health Services Research/Epidemiology

The objective of this project is to design and implement an effective community-based, culturally appropriate, lay self-management intervention for African-Americans with one or more chronic diseases, based upon the Chronic Disease Self-Management Program developed by Lorig and colleagues at Stanford.

Patients with diabetes are well known to be at greater risk than their normal counterparts for a variety of bacterial infections. The explanation for the excess risk is not yet clear.  The proposal is aimed at gaining evidence to support one of two hypotheses: l) that hyperglycemia itself plays a direct role via short-term effects on immune function, pathogen growth, or vascular permeability; 2) that the increased vulnerability is related to long-term effects of hyperglycemia on the microvascular system.  The candidate proposes to test these hypotheses through designing a program for much tighter glycemic control in patients undergoing cardiac surgery compared to the usual postoperative care.

The long-term objective of this project is to identify patient, provider, and system-level factors that can be targeted for intervention to reduce disparities in the utilization of joint replacement among minority veterans. The specific aims are: l)  to compare baseline surgical risk and predictors of surgical outcomes for non-Hispanic whites and ethnic minorities undergoing joint replacement; 2) to compare joint replacement outcomes between non-Hispanic whites and ethnic minorities, specifically African-Americans and Hispanics.

The proposal is to study the effectiveness of emergency department treatment protocols involving pediatric trauma patients in urban and rural [western U.S. state]. Using pediatric trauma protocols currently in use, the plan is to design a study to assess the efficacy of trauma protocol implementation specifically addressing pediatric fluid resuscitation in the urban and rural settings. With results of that study in hand the objective is to develop a scientifically rigorous protocol-implementation program to improve trauma treatment.

The goal of this project is to examine the impact of welfare reform on children with chronic illness. The hope is to provide useful information regarding welfare reform and child health to state and federal policy makers when the l996 Personal Responsibility and Work Opportunity Reconciliation Act (PRWORA) is discussed for reauthorization in 2002. The focus will be on chronically ill children because their increased health needs make them more vulnerable to changes in resources and access to health care.

This study will examine the benefits, risks, costs, and cost-effectiveness of alternative pancreatic cancer staging strategies. The working hypothesis is that utilizing endoscopic ultrasound to select patients for surgical exploration or endoscopic palliation will result in the greatest overall quality-adjusted life expectancy and cost effectiveness.