2013 — 2015 |
Rizzuto, Gabrielle A |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Immune Responses to Infection At the Maternal-Fetal Interface @ University of California, San Francisco
DESCRIPTION (provided by applicant): Pregnancy is a unique immunological situation because the fetus is not genetically identical to the mother. The placenta plays an important role in protecting the fetus from attack by the maternal immune system while at the same time protects the fetus from pathogens. The details of how the placental immune system accomplishes these seemingly contradictory tasks are largely unknown. Overview/Hypothesis: We hypothesize that the maternal immune cells of the placenta, specifically the macrophages located in the decidua (lining of the pregnant uterus), defend this organ against pathogens in a unique manner. Specific Aims: (1) To determine the decidual macrophage response to infection; (2) To investigate the role of IFN¿ and interferon-inducible proteins with tetracopeptide repeats (IFITs) in placental host defense. Methods: We will study the placental innate immune responses to the facultative intracellular bacterial pathogen Listeria monocytogenes (LM). LM infection during pregnancy in humans and other mammals leads to pregnancy complications such as preterm labor. In addition to its clinical relevance, LM is highly amenable to experimental analysis. We will utilize a combination of primary human and mouse placental macrophages and placental tissue in vitro to investigate how these cells respond to LM, and evaluate how their response differs from that of other tissue-specific macrophages (Aim 1). To confirm our findings in vivo, we will employ a pregnant mouse model. In addition to wild type mice, we propose to use mice with specific genetic backgrounds in order to dissect the role of cytokine signaling pathways (e.g. IFN¿) in the defense against placental infection (Aim 2). Training Goal: The other major goal for this F32 training award is the rigorous post-doctoral research training of Dr. Gabrielle Rizzuto in microbial pathogenesis and placental biology with the concerted use of human and murine research tools. Expected Results: We predict the results of this project will be (1) a clearer understanding of how the maternal immune system interacts with pathogens in the placenta; and (2) that the trainee will be well-positioned to begin a successful independent career as a physician-scientist. Relevance: The leading cause of newborn death worldwide is pre-term birth, and infection of the placenta is the most common cause of pre-term birth. We will begin to tackle this problem with a unique approach using primary human placental tissues and an important human bacterial pathogen, in conjunction with the pregnant mouse, a genetically tractable model to confirm and expand the in vivo relevance of our findings.
|
0.904 |
2018 — 2021 |
Rizzuto, Gabrielle A |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Maternal T Cell Recognition of Placental Antigen @ University of California, San Francisco
Project summary. The placenta sheds a vast amount of ?foreign? protein into maternal circulation during pregnancy, to be taken up and presented by maternal antigen presenting cells (APCs). Remarkably, the ensuing T cell response is neither immunogenic nor tolerogenic as pregnant mice neither become immunized to the antigen (Ag), even when given strong adjuvants and depleted of regulatory T cells, nor do they become tolerized to it. Thus, placental Ag is best considered ?non-immunogenic,? a potentially unique category without clear physiological antecedent. The objectives of this proposal are to elucidate the cellular and molecular basis for why placental Ag is non-immunogenic. This question is central to understanding how the placenta and fetus avoid immune rejection, and is also relevant to peripheral immune tolerance in general. As such it aligns perfectly with the long-term goal of Dr. Rizzuto which is to understand the immune pathogenesis of pregnancy complications and develop new therapies for use in transplantation, tumor immunology, and autoimmunity. The overall hypothesis of the proposal is that the non-immunogenicity of placental Ag can be explained by its physical/biochemical properties and/or the phenotype of the maternal APC, and has three specific aims. In Aim 1, Dr. Rizzuto will investigate the Ag presentation pathways governing CD4+ T cell responses and determine why these are non-immunogenic. This Aim builds upon preliminary data that B cells rather than DCs are critical for presenting placental Ag to maternal CD4+ T cells. In Aim 2, she will define the physical/biochemical properties of placental Ag that render it non-immunogenic, including exploring the functional significance of her finding that the Ag accumulates maternal antibodies. In Aim 3, she will define the Ag cross-presentation pathways that govern CD8+ T cell responses and determine why these are non- immunogenic. This Aim focuses on the classical Batf3-dependent DC subset known to cross-present Ag, as well as a currently undefined, and atypical APC. This work is relevant to the mission of NIAID because it will significantly expand the understanding of peripheral immune tolerance mechanisms. Dr. Rizzuto is an MD PhD research fellow at the University of California, San Francisco. She completed graduate work in tumor immunology and clinical training in anatomic pathology and is applying for a Mentored Clinical Scientist Research Career Development Award (K08). Her training plan will foster the attainment of her goal of becoming an academic physician scientist. This plan includes mentorship by Dr. Adrian Erlebacher, a leading expert in the field of reproductive immunology; scientific and career advisory by a multidisciplinary committee that includes leaders in the fields of immune tolerance and placental biology; coursework in reproduction, proteomics, and biostatistics; attendance at meetings to foster collaboration; and career development activities. These activities will provide Dr. Rizzuto with the necessary skills to merge her immunology research with her growing clinical expertise in perinatal pathology.
|
0.904 |