2009 |
Deshane, Jessy Satyadas |
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. |
Myeloid Regulatory Cells in Allergic Airway Inflammation @ University of Alabama At Birmingham
DESCRIPTION (provided by applicant): Hypothesis: Myeloid derived regulatory cells (MDRC), recruited to the lung during allergic airway inflammatory responses such as asthma, help to control the level of tissue inflammation by regulating the bioavailability of reactive free radicals, including nitric oxide (NO) and superoxide (02-). Specific Aims: (1) To test the hypothesis that myeloid subpopulations recruited to the lung of sensitized mice following antigen challenge generate and regulate the critical balance of reactive free radicals during allergic airway inflammation (2) Determine whether MDRC attenuate the asthmatic inflammatory response by mechanisms using reactive free radical species in a mouse model. Experimental Approach: C57BL/6, INOS-/- or B6 (Cg)-Ncf1m1 J/J mice will be sensitized intraperitoneally and challenged with the intranasal antigen, ovalbumin (OVA). Bronchoalveolar lavage (BAL) fluid and lung tissue will be examined for (1) dynamics of recruitment of MDRC (2) function of MDRC including phagocytic ability, and generation of cytokines and free radical species by MDRC. In addition, we will investigate (3) whether MDRC mediate suppression of T cell proliferation in vitro via iNOS, Arginase or NADPH oxidase pathways (4) whether MDRC mediate suppression of T cell proliferation following adoptive transfer in vivo and the role of NO and 02- in this effect, and (5) whether the adoptively transferred MDRC modulate airway hyper-responsiveness in a model of airway inflammation. Rationale: During allergic airway inflammatory responses, innate cells are recruited to the lung prior to adaptive immune cells. We present preliminary data to show (1) that two subsets of MDRC which generate O2- and NO are recruited to the lungs, and (2) MDRC suppress T cell proliferation via mechanisms that depend on free radicals, suggesting the potential for these cells to attenuate inflammation in vivo. Relevance to Public Health and the NHLBI Mission: The proposed studies will test directly the potential of MDRC to suppress asthma disease severity, potentially identifying novel targets for anti-asthmatic therapy.
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0.958 |
2012 — 2013 |
Deshane, Jessy Satyadas |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Myeloid-Derived Regulatory Cells in 'Atopic March' @ University of Alabama At Birmingham
PROJECT SUMMARY (See instructions): Objective: The overall goal of this proposal is to test the hypothesis that during allergic airway inflammation, epicutaneous sensitization induces Thymic Stromal Lymphopoeitin (TSLP), a cytokine biomarker for skin barrier defects, which then regulates the recruitment and function of free radical producing-airway myeloid - derived regulatory cells (MDRC), that are critical modulators of airway hyper-responsiveness (AHR). The proposed studies may uncover mechanisms linking MDRC and progression of atopic dermatitis to allergic rhinitis to asthma, the concept called atopic march. Specific Aims: (1) To test the hypothesis that route of allergen sensitization modulates the recruitment of airway MDRC during allergic airway inflammation via free radical dependent mechanisms (2)To determine whether increase in skin-derived or systemic TSLP levels regulates the activation and/or recruitment of 0 2 . - producing MDRC into allergic airway s and promotes AHR Research Design: Epicutaneous or intraperitoneal sensitization followed by intranasal challenge with ovalbumin induces allergic airway inflammation in the mouse model proposed in this study. MDRC will be analyzed and purified from bronchoalveolar lavage, lung tissue and secondary lymphoid organs at different time points following intranasal antigen challenge to determine their recruitment and function. Genetic knockouts and pharmacologic inhibitors of free radical pathways will be utiized to assess the free-radical mediated regulation of recruitment of MDRC and their potential to control T cell responses and AHR (measured by flexivent). The role of TSLP in modulating recruitment and function of MDRC will be delineated using anti-TSLP antibodies in conjunction with transgenic mice constitutively expressing TSLP. Rationale: Sub populations of NO- and 02.-producing mouse lung MDRC are master regulators of allergic airway inflammation. NO-producing MDRC suppress while 02.-producing MDRC enhances T cell responses and airway hyper-responsiveness. A balance in the ratio of immunosupressive and proinflammatory MDRC is critical for the control of inflammation. Recent studies indicate that high systemic levels of skin-derived TSLP is sufficient to render airway s hypersensitive to allergens. Studies to date have not investigated the potential role of TSLP in regulating the activation and/or recruitment of MDRC into allergic airway s. This study proposes a novel role for MDRC in understanding the relationship between skin barrier dysfunction and the pathogenesis of allergic asthma.
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0.958 |
2016 — 2020 |
Deshane, Jessy Satyadas |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Myeloid-Derived Regulatory Cells in Asthma @ University of Alabama At Birmingham
? DESCRIPTION (provided by applicant): Objective: The goal of this proposal is to investigate the novel concept that oxidant-modified self-peptides produced by free radical producing myeloid-derived regulatory cells (MDRCs) can trigger airway hyper- responsiveness (AHR). We recently characterized MDRCs as critical regulators of airway inflammation in both mice and humans. MDRCs use reactive oxygen and reactive nitrogen species (ROS and RNS) to enhance T cell proliferation and exacerbate AHR. Our recent studies show that MDRCs induce nitrative and oxidative modifications of self-peptides which are immunogenic neo-antigens for which tolerance has not been established. Consequently, these neo-antigens can elicit pathologic inflammatory responses that represent a novel form of autoimmunity. MDRCs thus are regulators of balance between tolerance and inflammation. In Aim 1, we will identify modified self-antigens/antigenic peptides produced by pro-inflammatory airway MDRCs in asthmatics. We will determine the peptide repertoire bound to HLA-Class II molecules of O2.-- producing airway MDRCs isolated from normal and asthmatic subjects, and define the ROS- and RNS-induced modifications of these self-peptides. These studies will be conducted by eluting the Class II-bound peptides from bronchoalveolar lavage (BAL) MDRCs, and identifying the nitrative and oxidative modifications of these peptides by mass spectrometry. In Aim 2, we will determine if modified self-proteins presented by ROS- producing MDRCs in asthmatics are true neo-antigens. Peripheral blood T cells and airway MDRCs purified from healthy and asthmatic subjects, and in-vitro modified self-proteins/peptides will be used in functional assays, limiting dilution analyses and co-cultures to investigate T cell proliferative responses, clonal proliferations and Th polarization. We will use a murine model of asthma to examine molecular mechanisms of MDRC-mediated Th polarization. These studies will provide evidence of a major role for MDRCs as regulators of immune tolerance and inflammation in asthma, and elucidate a new pathogenic paradigm for asthma. Identification of post- translational modified peptide neo-antigens can help define biomarkers to characterize asthma phenotypes. These studies also have the potential to enable development of new and improved therapeutic strategies to target MDRCs for disease control of subsets of asthma phenotypes (i.e., a precision/personalized medicine approach). We will obtain insight for potential novel peptide immunotherapy strategies targeting antigen- specific T cells with novel synthetic peptides representing modified T cell epitopes. .
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0.958 |
2021 |
Deshane, Jessy Satyadas |
P42Activity Code Description: Undocumented code - click on the grant title for more information. |
Project 2asthma in Children Exposed to Heavy Metals @ University of Alabama At Birmingham
SUMMARY Environmental exposure of the lung to airborne particulate matter (PM) containing mixed heavy metals contributes to development of chronic lung diseases, including asthma. These diseases are classically associated with dysregulated epithelial-mesenchymal communication. PM with a particulate size of ?2.5 µm (PM2.5) contain high levels of heavy metals, including cadmium (Cd), arsenic (As), and manganese (Mn). However, the mechanisms of how these heavy metals contribute to disease pathogenesis are unknown. In support of this project, we detected elevated levels of heavy metals in the serum/urine of residents from the Environmental Protection Agency (EPA) designated National Priorities List (NPL) Superfund site in North Birmingham. Asthmatic children from this Affected Area have evidence of systemic heavy metals exposure, as evidenced by higher urinary levels of arsenic. Bronchoalveolar lavage (BAL) fluid obtained by bronchoscopy of asthmatic individuals from this Affected Area contain epithelial cell-derived exosomes that package mitochondria. Additionally, BAL-derived exosomes from human asthmatic subjects are skewed towards a higher concentration of anti-apoptotic sphingolipids (sphingosine-1-phoshate > ceramide) by SWATH- lipidomics analysis. These exosomes are fibrogenic as they induce reprogramming of fibroblasts to an apoptosis-resistant and fibrogenic phenotype. Animal studies demonstrate that intra-tracheal instillation of heavy metals induces peribronchial fibrosis in mice, providing an opportunity to generate proof-of-concept pre- clinical data in support of targeting pro-inflammatory and pro-fibrotic sphingolipid pathways in environmental asthma. The hypothesis to be tested in this project is that heavy metal exposures in children induce airway epithelium injury/activation that triggers the release of exosomal lipids to activate fibroblasts/smooth muscle cells that contribute to airway hyper-responsiveness and remodeling in asthma. The specific aims are to: (1) determine the mechanisms of heavy metal-induced exosomal lipid signaling that activates sub-epithelial mesenchymal cells (SMCs/Fbs); (2) determine the role of lipid mediators/exosomes released by bronchial epithelial cells in airway hyper-responsiveness and remodeling in mice exposed to heavy metals; and (3) determine whether heavy metal exposures are associated with asthma severity and increased levels of plasma, EBC and sputum lipid biomarkers in children residing in the North Birmingham NPL Superfund site. These studies will provide new insights into the impact of heavy metal exposure on asthma susceptibility and severity; on novel mechanisms of epithelial-mesenchymal communication by fibrogenic exosomes; and development of new therapeutic approaches to the treatment of chronic asthma associated with heavy metal exposures.
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0.958 |