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Alix Berglund

Research Assistant Professor

CVM Main Building C305


Dr. Berglund received her BS in Zoology in 2010 and her DVM in 2014 both from Washington State University. She then completed her PhD in Comparative Biomedical Sciences at NC State in 2018 under the mentorship of Dr. Lauren Schnabel. Her PhD work was funded by a Morris Animal Foundation Fellowship and her postdoctoral work by an American Association of Immunologists Careers in Immunology Fellowship. Her current research on the immunogenicity of allogeneic mesenchymal stem cells is funded by her NIH K01 grant. Additional research interests include regulation of MHC expression and development of the horse as a large animal translational model for immunology research.


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Date: 12/15/19 - 11/30/23
Amount: $523,960.00
Funding Agencies: National Institutes of Health (NIH)

The proposed Mentored Research Scientist Development Award (K01) will provide the candidate, Dr. Alix Berglund, DVM, PhD, with the necessary knowledge, training, and experience to become an independent translational biomedical researcher in the fields of immunology and mesenchymal stem cell (MSC) biology. MSCs are a promising cell source for treating inflammatory and immune-mediated diseases. Allogeneic therapy would provide cost-effective and efficient treatment, but is currently hindered by recipient immune rejection of donor MSCs expressing mismatched-major histocompatibility complex (MHC) molecules. MSCs are strongly immunomodulatory, however, and manipulation of MHC expression may be sufficient to allow donor MSCs to evade recipient immune responses. The central hypothesis of this proposal, which is supported by strong preliminary research, is that treating MSCs with transforming growth factor-β2 (TGF-β2) downregulates MHC I and MHC II gene transcription thereby reducing the in vivo immunogenicity of MHC-mismatched MSCs. The aims of this project are to 1) Identify how TGF-β2 downregulates MHC expression in MSCs and 2) Determine how TGF-β2 treatment affects MSC immunogenicity in vivo. Both murine and equine MSCs will be utilized to elucidate TGF-β2 signaling pathways to increase translational potential to humans (Aim 1) and non-inflammatory and inflammatory murine models will be used to analyze how the immune system responds to TGF-β2-treated MSCs in vivo (Aim 2). Completion of the proposed research is a first step towards improving the efficacy and safety of allogeneic MSCs for clinical use. To accomplish these aims, Dr. Berglund will build on her background in mesenchymal stem cell biology, immunology, and large animal models by developing expertise in molecular immunology techniques, in vivo alloimmune response analysis, and the utilization of murine models. Dr. Berglund’s mentoring team has combined expertise in immunology, mesenchymal stem cells, and genetics to facilitate her transition to an independent translational biomedical researcher. This work will be completed primarily at the North Carolina State University College of Veterinary Medicine, which is eminently qualified to train translational clinician scientists, with additional work at the University of North Carolina-Chapel Hill.

Date: 09/01/19 - 8/31/20
Amount: $50,376.00
Funding Agencies: American Association of Immunologists (AAI)

Mesenchymal stem or stromal cells (MSCs) are of particular research interest due to their strong immunomodulatory capabilities, which contributes to the ability of MSCs to treat immune-mediated and inflammatory diseases [1]. MSCs have also been implicated in regulating tumor progression and metastasis [2]. We previously published that treating MSCs with 1 ng/ml TGF-beta2 decreased surface expression of MHC I [3] and our unpublished data supports that TGF-beta2 treatment decreases the cytotoxicity of MHC-mismatched MSCs in vitro. To determine the mechanism by which TGF-beta2 downregulates MHC I surface expression, we used RNA-sequencing on four untreated and four TGF-beta2-treated MSCs and found significant (p < 0.05) downregulation of beta2-microglobulin (B2M). MHC I gene expression was not significantly downregulated indicating that downregulation of B2M likely contributes to the reduced MHC I surface expression on TGF-beta2-treated MSCs. B2M noncovalently links to the alpha chain of the MHC I molecule and is necessary for stable MHC I surface expression [4]. In addition to its importance in antigen presentation, B2M is known to contribute to the metastatic potential of carcinomas, particularly when expressed by MSCs recruited to the tumor microenvironment [5]. In numerous types of carcinomas, B2M expression is abnormally increased and this promotes tumor cell proliferation and metastatic potential [6,7]. It has also been well documented that TGF-beta signaling is dysregulated in carcinomas and one study demonstrated that restoring TGF-beta signaling in ovarian carcinoma cells decreased B2M production leading to decreased proliferation and metastatic potential [8]. The ability of TGF-beta2 to downregulate B2M gene expression therefore appears to be a fundamental immunological mechanism important for regulating not only antigen processing and presentation, but also carcinoma tumor progression. The precise signaling pathways involved in this mechanism are unknown, but our preliminary data supports that it is dependent on TGF-beta Receptor I (ALK5) signaling. Elucidating how TGF-beta2 regulates B2M in MSCs may contribute to developing cancer therapeutics that can target this pathway as well as reducing the immunogenicity of donor MSCs to improve MSC regenerative therapies.

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