Ariana Darcy is a third year Molecular Medicine Student. Her mentor is Dr. Monty Montano, in the Section of Infectious Diseases and a Junior Faculty Member on this training program. Currently, her studies are focused on studying the observation that patients with HIV experience normal aging co-morbidities at an accelerated rate compared to uninfected age matched controls. More specifically, the potential role chronic inflammation and immunosenescence may play in the increased incidence of osteoporosis in these patients. She hypothesizes that chronic inflammation driven by HIV-1 infection contributes to bone loss in part due to 1) A defect in the BMP-2 signaling pathway of osteoblasts; and 2) An increase in senescent T cells that produce osteoblast inhibitor factors. She will be utilizing serum samples from the SUN (Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy) cohort to correlate inflammatory protein levels with bone mineral density scores previously obtained. She will also take advantage of the cohort of HIV positive women that the Montano laboratory has established at Boston Medical Center to measure osteoblast inhibitory factors in senescent CD4 and CD8 cells. However, to focus on the mechanism of chronic inflammation on osteoblast function, she will study the role of the inflammatory environment (using exogenous proteins and human sera) on BMP-2 signaling and BMP receptor expression levels. This should provide information that will be useful in understanding the indirect effects of chronic HIV infection.
Since being awarded a trainee on this program she has published her first manuscript in BONE, titled “A Novel Library Screen Identifies Immunosuppressors that Promote Osteoblast Differentiation” (Darcy, et.al. March 13 2012 Epub ahead of print). More recently she is also an author on a paper which was recently accepted paper “Premature Expression of a Muscle Fibrosis Axis in Chronic HIV Infection” in the journal Skeletal Muscle (Kusko et.al., accepted May 8 2012). Both of these projects have helped her establish an understanding in the physiology of bone and the potential mechanisms behind HIV induced accelerated aging.
Essence Maston is a third year Molecular Medicine student. Her mentor is Dr. Robin Ingalls in the Section of Infectious Diseases. Neisseria gonorrhoeae is the second most commonly reported reportable infectious disease in the United States. Transmission is almost exclusively by close sexual contact, and can occur at any mucosal surface, including the urethra, cervix, rectum and pharynx. In addition to localized disease, certain strains of gonorrhea are capable of dissemination, resulting in bacteremia, septic arthritis, and dermatitis (disseminated gonococcal infection or DGI). Infection with N. gonorrhoeae has also been associated with the development of pelvic inflammatory disease (PID) in women, which can lead to chronic pelvic pain, tubal infertility, and ectopic pregnancy. Finally, concomitant gonococcal infection has been shown to increase the risk of transmission of HIV both in vivo and in vitro. While overall rates of gonorrhea have decreased in recent years, significant disparities remain with regard to gender and race, with highest rates among African American women age 15 through 19. The goal of Ms. Maston’s project is to examine novel innate immune mechanisms that have an impact on transmission of gonococcal infection and the establishment of disease in women. Her project involves determining the importance of specific innate immune receptors, including the TLRs and inflammasome family members in two relevant cell types (neutrophils and endocervical epithelial cells). Her project takes advantage of a novel 3-dimensional tissue model of human endocervical epithelium, and a mouse model for infection established in the Ingalls laboratory. The aims of her thesis project are as follows: 1) To further define the role of neutrophils and innate immune receptors, includingTLR4, in gonococcal pathogenesis; 2) To further define the innate immune pathways activated during infection of endocervical tissue and endocervical epithelial cells; and 3) To characterize the mechanism of gonococcal invasion into endocervical tissue. Ms. Maston is an underrepresented minority student.
Tuan Pham is a third year student in the Department of Biomedical Engineering. His research mentor is Dr. James Hamilton in the Department of Biophysics. Mr. Pham’s research project involves serial MRI of rabbits with induced atherosclerosis in order to evaluate the efficacy of therapeutic agents. His project involves both biomedical engineering aspects and immunological assessment of inflammatory mediators that predict clinical outcomes. The idea is to create advanced atherosclerotic lesions in the rabbit, and image the plaques over time, while providing treatment. With the MRI data, they will be able to obtained characteristics of these plaques and determine if and how the therapeutic agents affect each characteristic (vessel area, vessel wall area, lumen area, remodeling ratio, gadolinium uptake, etc.). Of note are that the MRI scans are performed prior to and after the treatment. After the treatment protocol plaque rupture is triggered to determine whether or not the therapy has affected the instances of ruptures. Immunological markers are assessed at the conclusion of the MRI. This analysis will allow for the differentiation between vulnerable and stable plaques and will provide a baseline to track the effects of therapy on plaque progression.
Connie Slocum is a third year Molecular Medicine student in Dr. Caroline Genco.’s laboratory in the Department of Medicine, Section of Infectious Diseases. Connie’s project is focusing on understanding basic mechanisms of pathogen induced chronic inflammation. Chronic inflammation culminates in devastating events, results in significant host pathology, and is associated with a number of human diseases including autoimmune, infectious, neoplastic diseases and inflammatory atherosclerosis. P. gingivalis has been implicated in the pathogenesis of chronic inflammatory plaque formation, although how this pathogen induces and maintains chronic inflammation is not well defined. Studies from the Genco laboratory as well as others have implicated specific innate immune signaling pathways in P. gingivalis mediated inflammatory atherosclerosis. The pro inflammatory cytokine IL-1 has been documented to play a role in chronic inflammation associated with chronic inflammatory plaque formation in mice. Additionally, it has been shown that P. gingivalis, through modifications of its Lipid A, can differentially activate TLR-4 leading to differences in IL-β secretion. It is unclear what role IL-1 and modified Lipid A of P. gingivalis play in both the chronic inflammatory plaque accumulation induced by P. gingivalis and what immune cells contribute to this response. The goals Connie’s project will be to define the role of IL-1 in chronic inflammatory plaque accumulation in response to P. gingivalis infection, from both wild type and mutant lipid A strains, and specifically will define which immune cells contribute to this response. Understanding the cell signaling networks involved in inflammation will provide a promising avenue for novel therapies for chronic inflammatory disorders and specifically atherosclerosis induced by bacterial infection. Funds from the Inflammatory Disorders Training Grant allowed me to attend two conferences this spring.
Elaine Lee is a postdoctoral trainee in the laboratory of Joyce Wong in the Department of Biomedical Engineering in the College of Engineering. Work in the Wong laboratory is focused on replicating native blood vessels with anisotropic contractile properties using cell sheet engineering technology to replace blood vessels damaged by the chronic inflammatory response in atherosclerosis. Cell sheet technology allows for complete, non-damaging recovery of cell sheets, which allows these sheets to be layered to form a construct without the use of polymeric scaffolding that may cause inflammatory responses. However, although current technologies may allow cell sheets to be recovered with intact alignment, the sheets are fragile; mechanical conditioning of these sheets may allow replication of the native mechanical properties. Previously, with the aid of a trainee’s American Heart Association Predoctoral Fellowship, a device was created using a silicone elastic membrane that can mechanically condition cells for cellular alignment and secretion of proteins and extracellular matrix (ECM) components, and then allow for a thermo responsive spontaneous, non-damaging detachment of those cells and secreted ECM fully intact for a scaffold-free cellular implant. They aim to take the next step in engineering functional tissue engineered blood vessels by creating cell sheet monolayers with controlled ECM growth, which are subsequently stacked and rolled to create a durable blood vessel for implantation. Their first aim was intended to compare cellular alignment of cells mechanically conditioned anisotropically to nonconditioned cells aligned on patterned substrates that were made previously in the Wong laboratory. However, it was soon discovered that these substrates have nonuniform cellular attachment and detachment, which may indicate that the thermo responsive polymer may be unevenly grafted. They currently are performing surface analysis using x-ray photoelectron spectroscopy (XPS) to measure the atomic concentration of nitrogen, a key element indicating the presence of the successfully grafted thermo responsive polymer.