| 2008 — 2012 |
Tomayko, Mary |
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. |
Elucidating Functional Properties of Memory B Cells
[unreadable] DESCRIPTION (provided by applicant): Memory B cells that differentiate into antigen presenting and antibody-producing cells are important for long-term immunity to natural antigens and vaccines and may play a key role mediating the clinical manifestations of autoimmune diseases. Memory B cells themselves, however, are typically rare and hence poorly understood. Using mouse systems developed in our laboratory that overcome significant barriers to the study of B cell memory, we compared gene expression between memory B cells and their naive precursors using Affymetrix microarrays and have confirmed the differential expression of several conceptually important families at the mRNA and protein level. Based on known functions of these genes in other cell types, we have developed hypotheses about how their functions determine properties of memory B cells. Here, we propose to test the hypotheses that: 1) leukemia inhibitory factor signaling regulates memory B cell self-renewal and differentiation and 2) the B7 family member PD-L2 on memory B cell plays a central role modulating the secondary response to antigenic stimulation. In the long-term, a better understanding of the events required for memory B cell self-renewal, differentiation and activation will lead to improved vaccination strategies. My immediate career goal, is to acquire the training and develop the systems required to address these hypotheses of B cell memory as an Assistant Professor of Dermatology at Yale. This proposed 5-year mentored program will provide the basis for many long-term projects and collaborations and will foster my development into an independent investigator. RELEVANCE: The ability to develop "immunological memory" to infectious diseases is critical for health and survival. These proposed studies will help elucidate how "memory" functions in order to better understand natural immunity and improve vaccine design. [unreadable] [unreadable] [unreadable]
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0.915 |
| 2015 — 2019 |
Tomayko, Mary |
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. |
B Cell Memory Regulation by Bone Morphogenetic Protein Receptor 1a
? DESCRIPTION (provided by applicant): The mechanisms that underlie effective B cell memory formation, maintenance and function are poorly understood. We have a long-standing interest in this area and have made significant contributions. Here, we describe intriguing observations suggesting that activation of bone morphogenetic protein receptor 1a (Bmpr1a) is critical in the germinal center reaction and is required for the development of long-lived bone marrow plasma cells (BMPC) and memory B cells (MBC). As Bmpr1a, a TGF-ß family receptor, transduces signals that regulate self-renewal and differentiation decisions in several stem cell populations, we hypothesize that it plays analogous roles in GC B cells (GCB) and MBC as well. The first part of the proposal addresses the role of Bmpr1a activation in GCB function and in the formation of BMPC. We ask if Bmpr1a activation regulates proliferation or apoptosis of GCB and if its activation is directly required for differentiation of GBC to BMPC. We also propose construction of a Bmpr1a fluorescent reporter mouse to ask if Bmpr1a expression is a characteristic of all GCB or a restricted subset, suggesting a specialized function of Bmpr1a+ GCB. The second part of the proposal addresses the role of Bmpr1a activation in MBC and BMPC. We will determine if this pathway enables MBC to self-renew and if it supports the long-term survival of BMPC. We will also ask if, in the secondary response, Bmpr1a directly regulates MBC differentiation to PC. Finally, using the Bmpr1a reporter mouse created in Aim 1, we will ask if Bmpr1a expression is restricted to a subpopulation of MBC. The finding of restricted expression amongst MBC would be intriguing, suggesting that the ability to activate Bmpr1a signaling confers special properties to MBC, such as the potential to self-renew. Alternatively, if Bmpr1a expression is a general property of MBC, Bmpr1a expression and these Bmpr1a.eGFP reporter mice particularly will be valuable tools for tracking and isolating rare MBC. In summary, we propose to investigate the role of a conserved stem cell pathway in the formation, maintenance and function of B cell memory. Bmp signaling has been studied little in B cell biology, so this work is novel. The findings are of potentially high significance to the fundamental understanding of the function of the adaptive immune system and may influence vaccine design. The data generated and the model systems created will lay the foundation of future work.
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0.915 |