CBR Research Grants
Project Summaries—2011
2011—2010—2009—2008—2007—2006—2005—2004—2003—2002—2001—2000—1999—1998—1997—1996—1995
Weight Loss and Change in Mammographic Density The Effect of Liraglutide With or Without Aerobic Exercise on Endothelial Dysfunction and Vascular Reactivity in Patients with Pre-diabetes The Role of Hepoxilins and Neutrophils in Infectious Asthma The Massachusetts BMI Letter: How are Parents Responding? Protein Expression Patterns in Primary and Metastic Breast Carcinoma
Targeted Delivery of Nanomaterials by Wound Homing Cells |
Weight Loss and Change in Mammographic Density Mammographic breast density is a strong risk factor for breast cancer, making it a possible surrogate endpoint in etiologic studies. It can be quantified as the absolute amount of dense breast tissue or as the percentage of the breast comprised of dense tissue. Weight loss/maintenance decreases breast cancer risk. Obesity increases risk of postmenopausal breast cancer, yet decreases percent density. This incongruous relationship must be understood before density can be used as a breast cancer biomarker. Such knowledge also will elucidate the mechanisms involved in body weight’s effects on breast cancer risk. In this prospective study of weight loss and mammographic breast density, we will collect mammograms and measure height/weight over one year on 200 women age ≥40 who are either pursuing bariatric surgery or not attempting to lose weight. Participants will be recruited from the Weight Loss Surgery Program and the Comprehensive Breast Center at Baystate Medical Center. Participants will attend two clinic visits; at each visit they will have a mammogram taken, have their height and weight measured, and complete a brief questionnaire. The visits will be timed such that the mammograms will also be the participants’ annual screening mammogram. The second clinic visit will occur one year after the first clinic visit. We hypothesize that women with the greatest weight loss will have a greater decrease in dense breast area yet also a greater increase in percent density. This research will improve our understanding of the relationship between body composition and breast cancer development. Effective date: 2011 The Effect of Liraglutide With or Without Aerobic Exercise on Endothelial Dysfunction and Vascular Reactivity in Patients with Pre-diabetes The American Diabetes Association reports that macrovascular complications, namely coronary artery disease and stroke are 3 times more common in Prediabetics compared to normal subjects. Therefore, targeting and optimizing therapies for prediabetics is an important component for the prevention of diabetic cardiovascular complications and the progression to overt diabetes. Glucagon Like Peptide-1 (GLP) agonists have been used in the treatment of diabetes since 2005. While GLP-1 agonists help reduce weight, reduce gastric emptying, increase insulin sensitivity, response and possibly secretion in humans, little is known about their cardiovascular effects. Exercise training is regarded as a potent therapy enhancing glucose metabolism in patients with diabetes, however the efficacy of exercise training to alleviate vascular dysfunction pertaining to prediabetes is unclear. Therefore, evaluating the cardiovascular effects of GLP-1 agonists alone or in combination with exercise training may allow physicians to refine therapies in patients with pre-diabetes. The purpose of this study is to investigate if a once daily injection of GLP-1 agonist (ie, Liraglutide) alone or in combination with aerobic exercise for 13 weeks improves endothelial function and prevents the progression of pre-diabetes to diabetes and decreases cardiovascular risk. Effective date: 2011 The Role of Hepoxilins and Neutrophils in Infectious Asthma Asthma remains an incurable disease that affects over 300 million people worldwide, including ~24 million Americans. It is well known that asthma is a multifactorial disease characterized by episodes of wheezing, coughing, and shortness of breath. Besides well-defined environmental and genetic risk factors, accumulating evidence suggests that respiratory infections play an important role in asthma severity and possibly its initiation in a subset of patients. Recent studies from our lab have shown that early life Chlamydia pneumoniae infection is associated with increased incidence of childhood asthma. Asthmatics with C. pneumoniae lung infection also have significant infiltration of neutrophils, a phenomenon not often seen in typical aeroallergen-induced asthma. Neutrophil are the bodies first line of defense against bacterial infections but local accumulation can lead to significant tissue pathology. Recent reports suggest that under certain conditions, neutrophils can produce and release histamine, a significant vasoactive amine which is responsible for smooth muscle contraction, narrowing of the airways, severe inflammation and mucus secretion; the hallmarks of asthma pathology. Almost 50% of current persistent asthma cases are accompanied by an increase in airway neutrophils. These patients are more likely to have continuous asthma attacks and be unresponsive to even high doses of inhaled corticosteroid. This is also the subset of asthmatics at greatest risk for asthma-related deaths, suggesting an important pathologic role for neutrophils. Currently, it is not known which host product induced by C. pneumoniae and possibly other infectious agents result in neutrophil infiltration in the asthmatic lungs. Hepoxilins are biologically active metabolites which are released upon tissue damage and were recently identified as potent neutrophil chemoattractants in the intestinal mucosa. We therefore hypothesize that neutrophils migrate from the circulation into the C. pneumoniae-infected airway because of the release of hepoxilins, resulting in airway inflammation and pathology. The goal of the current study is to utilize an animal model as well as patient samples to test this hypothesis. We hope to prove that there is an infectious asthma phenotype that can be induced by Chlamydia. If hepoxilin is released as a consequence of airway infection, regulation of airway hepoxilin might provide a novel therapeutic strategy for a significant percentage of asthmatics who are at increased risk for asthma mortality. The proposed research therefore has the potential to lead to targeted therapeutics aimed at reducing neutrophil trans-epithelial migration (hepoxilin antagonists and Chlamydia antibiotics) for hard-to-control asthma. Effective date: 2011 The Massachusetts BMI Letter: How are Parents Responding? In 2009, Massachusetts became the 16th state to pass BMI-related legislation as part of a wave of support for BMI monitoring, both as part of Mrs. Obama’s Let’s Move programand Healthy People 2020 objectives. As mandated, during 2010-2011 school nurses will collect height and weight data of 1st, 4th, 7th, and 10th graders; calculate their BMIs; and send a BMI screening report (BMISR) with each student’s results to parents/caregivers with recommendations to contact their primary care provider. Parents’ ability to understand the BMISR is vital to the BMISR success, but to date there has been no substantive evaluation of how this information is understood by parents. In this study, we will evaluate the readability of the BMISR and hold focus groups with parents to assess reactions to and understanding of the BMISR. This research puts Massachusetts in a leadership position to contribute to efforts to prevent and reduce childhood obesity, increase health knowledge and skills of families and health care providers, and ultimately reduce health costs. Effective date: 2011 Protein Expression Patterns in Primary and Metastic Breast Carcinoma Breast cancer is the most frequently occurring cancer in women and between 12% and 13% of women will develop invasive breast cancer over the course of their lifetime. Cancer results from cellular mutations that enhance cell division, decrease tumor suppressive signals, and decrease programmed cell death; and from cellular alterations that enhance local blood flow to tumors (angiogenesis) and metastasis to distant organs. Notably, metastasis is the most deadly aspect of breast cancer and takes place when invasive epithelial cells in a primary tumor leave their site of origin, digest and break through the extracellular matrix, migrate into blood vessels, and invade secondary sites. In addition different types of carcinomas have different site predilections to metastasize to. In this study we will examine the expression of multiple proteins (CaSR, PTHrP, RANKL, SFRP1) that have been implicated in tumor metastasis by immunohistochemical technique in primary breast carcinomas, and their lymph node and distant organ and bone metastases. Our main questions are: 1) are the selected proteins expressed/conserved in tumor metastases when compared to the primary tumor; 2) is there a difference of expression of the selected proteins among the different metastatic sites. We will determine the relationship of the above findings with known tumor predictors of clinical outcome (eg. tumor grade, size, hormonal ER and PR status, and HER-2/neu status). To establish the characteristics of the interrelationship between the selected proteins we will use an experimental model. We will look at the expression pattern of CaSR, PTHrP, and RANKL in a SFRP1 knockout mouse model (animals that do not express SFRP1) to determine the effect of SFRP1 loss on these protein expression patterns. Analyzing the characteristics of expression of these proteins in primary breast carcinoma and in the respective distant metastatic foci may help in the understanding of the molecular mechanisms involved in metastatic spread of malignant tumors, and aid in designing new therapeutic strategies/interventions to inhibit this process. Effective date: 2011 Targeted Delivery of Nanomaterials by Wound Homing Cells
Certain cell types will inherently home to sites of inflammation to aid in the healing process, and there is an opportunity to exploit such homing characteristics to deliver healing peptides and small molecules to tumors, as well as wounds. Working collaboratively, Schneider, Emrick, and Arenas will test the concept that one can link polymer prodrugs to these cell types to realize improved drug targeting to tumors or wound sites. The collaborative team will investigate polymer-drug constructs for conjugation to stem cell or progenitor cells, and subsequently evaluate conjugate stability, toxicity, and effects on chemotactic movement. Schneider and Arenas will further test in vivo whether the cells can direct cargo to specific locations, giving a versatile platform for wound care and cancer treatment. Effective date: 2011 |