Round 5: 2016-2017 Pilot Projects
Adipose Stromal Cells from Obese Donors Promote Tumorigenesis and Metastasis of Breast Cancer
Co-Principal Investigator: Matthew Burow, PhD, Tulane University
The negative impact of obesity on human health is clear. Presently in Louisiana over
35% of adults are obese (BMI 30). If you look at rate of obesity in Louisiana by race
30.5% of Caucasians and 43.2% of African Americans are impacted. Obesity is directly
linked to an increased cancer incidence, progression and patient mortality in a number
of cancer types including breast. In Louisiana, the number of cases of obesity-related
cancers is more than 70,000 per year and it is projected that by the year 2030 that
incidence will increase to more than 170,000 per year. Obesity significantly increases
breast cancer mortality particularly in Triple Negative Breast Cancer (TNBC) which
is defined by a lack of estrogen receptor (ER), progesterone receptor (PR), and Her2/Neu
over-expression. TNBC occur more frequently in younger patients, are more aggressive
than other molecular subgroups and have a higher prevalence in African-American women.
Understanding the mechanisms by which obesity affects breast cancer progression and
patient survival is a significant public health issue with clear health disparities
in Louisiana. Our collaborative team has designed experiments that will clarify the
role obesity plays in the tumor microenvironment and specifically in TNBC progression
and metastasis. We have defined a previously unrecognized role of adipose stromal/stem
cells (ASC) in controlling breast cancer progression and metastasis. ASCs are stem
cells of mesenchymal origin found in adipose tissue that give rise to adipocytes.
During the development of breast cancer, these cells are recruited to the tumor and
are essential components of the tumor stroma. Our preliminary data demonstrates that
both tumorigenesis and progression are the result of communication between the stroma
and the tumor cells. We found that obesity fundamentally alters adipocyte and ASC
biology, and that the cross -talk
between obesity altered ASCs and tumor cells results in a dramatic induction of tumor growth, progression and metastasis. A thorough understanding of the impact of obesity on these tumor stroma interactions and ultimately tumor incidence and progression is of great significance. The objective of this pilot proposal is to define the molecular pathways by which obASC directly alter the tumorigenicity and metastasis of BC tumor microenvironment. The data collected form these preliminary studies will provide essential data on the impact of ASCs from obese individuals on TNBC, which impacts the African-American population, using patients collected from Louisiana citizens.
Using a Community-Favored Alternative Research Design to Study How Neighborhoods May Be Promoting Health Disparities
Co-Principal Investigator: Robert Newton, PhD, Pennington Biomedical Research Center
This study is unique in that it aims to examine experimentally whether children who live in neighborhoods less supportive of physical activity having higher crime and lower access to parks experience lower increases in physical activity when they participate in an intervention. Also, this study explores using a novel, community-favored research design that provides scientific rigor on par with traditional designs, while also allowing all participants to receive the intervention. Results will support a larger study to answer the question of whether the environment can impact a physical activity program's success and will identify ways to promote physical activity in unsupportive environments. Because poorer and minority populations tend to live in less-supportive neighborhood environments, these results will be important for efforts to reduce health disparities in physical activity and related diseases.
Cross-generational Cardiovascular Risk Factors: Bogalusa Daughters
The Developmental Origins of Disease hypothesis has spurred increased interest in how prenatal exposures affect lifelong health. In this project, we will draw upon the data, specimens, and infrastructure of the Bogalusa Heart Study, a long-running study of life-course cardiovascular health in semirural, biracial population (65% white and 35% black). The study provides a research base with unique information about multigenerational influences on cardiovascular health. Our specific aims are: 1) To examine the relationship between mother's pre-pregnancy and daughter's adolescent/young adult cardiovascular health; 2) To examine whether a woman's cardiovascular health predicts birth outcomes of their grandchildren; and 3) To examine the relationship between mother and daughter's reproductive health. Pre-pregnancy weight, blood pressure, lipids, and glucose levels and pregnancy weight gain will be examined separately and jointly as predictors. This project will provide insight into health disparities for important outcomes such as obesity, diabetes, high blood pressure, and low birthweight, that have high prevalence in Louisiana.
Lifespan Cardiovascular Exposures and Risk of Brain Injury in the Bogalusa Heart Study
Co-Principal Investigator: Owen Carmichael, PhD, Pennington Biomedical Research Center
Cardiovascular disturbances accumulating throughout the lifespan promote sub-clinical brain injury later in life, increasing risk for adverse outcomes including cognitive decline, dementia, stroke, depression, gait disturbance, and early mortality. Unfortunately, the relationship between cumulative exposure to cardiovascular conditions and brain health is under-studied due to difficulty in prospectively collecting cardiovascular data across the lifespan. The Bogalusa Heart Study has 40 years of detailed assessments from childhood through adulthood in a semirural, biracial community, and since 2012, cognitive performance. In the proposed project 50 participants with varying lifespan cardiovascular risk will undergo MRI, including measures of brain tissue volumes, lesion burden, white matter integrity, infarction, cerebral perfusion, and functional and structural connectivity. The association between cumulative cardiovascular exposures and MRI-based measures of brain injury will be assessed to determine optimal design of the definitive study that systematically determines how lifespan exposures impact brain health in the entire cohort of 1,298 participants.
Clinical Impact of Ethnic Variation in Mitochondrial Function on Hypertension
Hypertension is an increasing health concern in the United States and African Americans are at a higher risk for hypertension, develop hypertension at an accelerated rate, and are more likely to have uncontrolled hypertension in spite of treatment. Reactive oxygen species (ROS) are important mediators in hypertension development and a limited number of studies support ethnic differences in ROS production demonstrating that African American cells produce more ROS compared to Caucasians. We hypothesize that ethnic variation in mitochondrial function and increased ROS production in monocyte/macrophages contribute to hypertension by promoting vascular inflammation and ultimately vascular and renal dysfunction. Our proposed study will be the first to investigate how variation in mitochondrial function contributes to hypertension amongst ethnicities in healthy and hypertensive individuals. Results from these studies may identify novel therapeutic targets for the development of individual treatment strategies for those with increased incidence of or resistant hypertension.
Developing New Ceramide Analogs as Therapeutic Agents Against AIDS-related Lymphomas
HIV+ individuals have a greatly increased risk of developing malignancies including AIDS-related lymphoma (ARL), which is currently the most common type of cancer in HIV+ individuals in the USA. ARL have a variety of subtypes, such as Diffuse large B-cell lymphoma (DLBCL) and Primary effusion lymphoma (PEL), many of which are related to oncogenic virus Epstein-Barr virus (EBV) or Kaposi's sarcoma-associated herpesvirus (KSHV) infection while still lacking of specific treatment. Ceramide serves as a central mediator in sphingolipid metabolism and is referred to as a tumor suppressor lipid, however, its role in ARL and therapeutic evaluation remain largely unknown. In the current study, we plan to assess the anti-cancer activities of our newly synthetic ceramide analogs as lead-compounds in ARL especially those virus-associated subtypes in vitro and in vivo, as well as understand the underlying mechanisms.
Assessment of Unmethylated Insulin DNA with Droplet Digital PCR in Adolescents with Type 2 Diabetes Compared to Adolescents with Type 1 Diabetes and without Diabetes
Droplet digital PCR (ddPCR) is an advanced technology which has been applied to detect circulating insulin gene DNA in the bloodstream. The only significant source of insulin gene DNA is through death of pancreatic -cells; therefore, the level in the bloodstream is proportional to the degree of cell death. This technology has been applied to patients with type 1 diabetes and their relatives as a marker of cell decline. Type 2 diabetes diagnosed during adolescence appears to be more aggressive compared to diabetes diagnosed during adulthood. One hypothesis is that loss of the insulin-producing cells ( -cells) in the pancreas contributes to early treatment failure. The purpose of this pilot study is to validate the ddPCR technology and to determine the degree of -cell death in adolescents with type 2 diabetes in correlation with -cell function measured via a mixed meal tolerance test. The ability to identify this pathophysiology in adolescents with type 2 diabetes may be important in determining more aggressive treatment earlier in the disease course and could predict early future complications.
Can Carnitine Supplementation Suppress Fructose-induced de Novo Lipogenesis (DNL)?
Co-Principal Investigator: Eric Ravussin, PhD, Pennington Biomedical Research Center
This proposal is an interdisciplinary collaboration with the goal of testing in humans (Ravussin) the exciting preclinical observation (Mynatt) of the beneficial effect of carnitine supplementation on metabolic health. Over consumption of high fructose corn syrup is a risk factor for the development of obesity, diabetes, and the transition from fatty liver to NAFLD and NASH. Many of the deleterious effects of fructose consumption are caused by the rapid and largely unregulated oxidation of fructose by the liver causing acetyl-CoA overload and increased DNL. Dr. Mynatt’s preclinical data demonstrates that L-carnitine robustly scavenges excess acetyl-CoA as acetyl-carnitine. In a randomized clinical trial, we will test the ability of carnitine supplementation to suppress fructose-induced DNL. This will be the first clinical study to test the ability of carnitine supplementation to reduce fructose toxicity. This pilot project translates PBRC animal model findings to human subjects and will provide preliminary clinical proof that carnitine may improve metabolism
A Pilot Study to Improve Patient Outcomes Among Breast Cancer Patients by Increasing Early Detection and Intervention of Cardiotoxicity
In conjunction with women being diagnosed earlier with breast cancer and a rapidly aging population, advances in cancer therapies have swiftly propelled cardiotoxicity as a major health concern. Early markers of myocardial change are a necessity to identify patients experiencing cardiotoxicity so interventions to preserve and save myocardial function can be employed. The proposed pilot study will determine the feasibility of early detection and treatment of cardiotoxicity of three prevalent breast cancer chemotherapy regimens in a sample of 20-25 stage 1-3 primary site breast cancer patients initiating chemotherapy without prior radiation therapy. Cardiotoxicity will be determined by biomarkers and echocardiography measuring global longitudinal strain. Patients will be followed prospectively with data ascertainment at baseline, after the 2nd and 4th chemotherapy cycles of chemotherapy. Patient and physician focus groups will also be used to collect qualitative data regarding patient experiences and physician practices. This study will start to address the priority of maximizing benefits while reducing cardiac risks in oncologic management and survival.