BIOMEDICAL SCIENCES GRADUATE PROGRAM SPRING 2017

Transcription

1 THE OHIO STATE UNIVERSITY BIOMEDICAL SCIENCES GRADUATE PROGRAM SPRING 2017 Stephen M Bergin PhD Candidate Activation of Hypothalamic BDNF Modulates Lymphocyte Immunity February 17 th, 2017 Room 105, Biomedical Research Tower 1:00pm

2 VITA 12/24/ Born, Dayton, OH 05/21/ Bachelor of Science, Chemistry, Duke University 2011-present M.D., Ph.D. Candidate The Ohio State University COMMITTEE MEMBERS Michael A. Caligiuri, M.D., Advisor Lei Cao, Ph.D. Jian Hua Yu, Ph.D. Russell R. Lonser, M.D.

3 ABSTRACT Macro-environmental factors, including a patient's physical and social environment, play a role in obesity, cancer risk, and tumor progression. Living in an enriched environment (EE) providing complex stimuli leads to improved cognitive and metabolic health, and our previous studies show that EE confers anti-obesity and anticancer phenotypes in mice. These phenotypes are mediated in part by a specific brain-fat, neuroendocrine axis, with brainderived neurotrophic factor (BDNF) as the key brain mediator, whose upregulation elevated sympathetic tone preferentially to the white adipose tissue leading to the induction of beige cells and the robust reduction of leptin production and secretion. We investigated how an EE modulated T-cell immunity and its role in the EE-induced anticancer effects. Our data demonstrated that CD8 T cells were required to mediate th e anticancer effects of an EE in an orthotropic model of melanoma. In secondary lymphoid tissue (SLT), an EE induced early changes in the phenotype of T-cell populations, characterized by a decrease in the ratio of CD4 T helper to CD8 cytotoxic T lymphocytes (CTLs). Overexpression of hypothalamic BDNF reproduced EE-induced T- cell phenotypes in SLT whereas knockdown of hypothalamic BDNF inhibited EE-induced immune modulation in SLT. Both propranolol and mifepristone blocked the EE-associated modulation of CTLs in SLT suggesting both the sympathetic nervous system and hypothalamic-pituitary-adrenal axis were involved. Our results demonstrated that enhanced anticancer effect of an EE was mediated at least in part through modulation of T-cell immunity and provided support to the emerging concept of manipulating a single gene in the brain to improve cancer immunotherapy. Diet-induced obesity (DIO) promotes a pro-inflammatory microenvironment within visceral adipose tissue (VAT), but the molecular interactions regulating VAT and immune cells are

4 mostly unknown. Innate lymphoid cells (ILC) are a newly characterized immune cell present within the VAT microenvironment, which regulates adipocyte insulin sensitivity and energy expenditure and represents a cellular target for treating obesity. We investigated how the EE modulated the homeostasis of ILC frequency within the VAT microenvironment. EE increased ILC numbers and frequency within VAT compared to SE mice. Overexpression of hypothalamic BDNF in SE mice increased the frequency and number of ILCs in VAT, demonstrating the sufficiency of hypothalamic BDNF to reproduce the EE-ILC phenotype. In DIO mice, the increase of ILC frequency within VAT-associated with EE was maintained and associated with an improved metabolic phenotype. This ILC increase was induced independently of activation of the hypothalamic-pituitary-adrenal stress axis. Overall, our results suggest that EE regulates ILC function and homeostasis within VAT and can be therapeutically targeted to treat obesity.

5 RECENT ABSTRACTS AND PRESENTATION Bergin SM, Xia R, Judd R, Cao L, Caligiuri MA. Hypothalamic BDNF controls ILC2 homeostasis in adipose tissue and leptin regulates ILC2 function. Poster Presentation, Society for Natural Immunity. Taormina, Italy. October Bergin SM, Xia R, Judd R, Cao L, Caligiuri MA. Hypothalamic BDNF controls ILC2 homeostasis in adipose tissue and leptin regulates ILC2 function. Poster Presentation, Keystone Symposia: Immunometabolism in Immune Function and Inflammatory Disease. Banff, Alberta. February Bergin SM, Liu J, Bradley D, Blaszczak A, Wang Q, Wright V, Judd R, Caligiuri MA, Hsueh W. Alterations in Visceral Adipose Tissue Innate Type 2 Lymphoid Cells (ILC2s) as Determinants of Metabolic Health in Obese Patients. Poster presentation, 76 th American Diabetes Association Annual Meeting, New Orleans, LA. June Bergin SM Run Xiao, Ryan Judd, Huang Wei, Lei Cao, Michael Caligiuri. Genetic and environmental activation of hypothalamic BDNF alters the adipose tissue immune microenvironment". Poster presentation, Annual OSUMC Trainee Research Day, Columbus, OH. April Bergin SM Run Xiao, Ryan Judd, Huang Wei, Lei Cao, Michael Caligiuri. Genetic and environmental activation of hypothalamic BDNF modulate Tcell immunity to inhibit tumor growth". Poster presentation, Annual OSUMC Trainee Research Day, Columbus, OH. April 2015.

6 RECENT PUBLICATIONS Xiao R*, Bergin SM*, Huang W, Slater A, Judd R, Scoville S, Chen L, Caligiuri MA, Cao L. Environmental and genetic activation of hypothalamic BDNF modulate T-cell immunity to exert an anticancer phenotype. Cancer Immunology Research PMID: *Indicates co-first authorship Bergin SM*, Xiao R*, Huang W, Slater A, Judd R, Chen L, Caligiuri MA, Cao L. Environmental and genetic activation of hypothalamic BDNF modulates the adipose immune microenvironment to improve metabolic health. In preparation Deng T, Lyon C, Liu J, Bradley D, Blaszczak A, Wright V, Bergin SM, Hsueh W Adipocyte MHCII stimulates diet-induced adipose inflammation and insulin resistance by decreasing regulatory T cell abundance in adipose tissue Nature Communications. Under review Scoville SD, Mundy-Bosse BL, Zhang MH, Chen L, Zhang XL, Keller KA, Hughes T, Cheng S, Bergin SM, McClory S, Yu JH, Carson, WE 3rd, Caligiuri MA, and Freud AG. A progenitor cell expressing transcription factor RORgt generates all human innate lymphoid cell subsets. Immunity PMID: Alvarez-Breckenridge CA, Yu J, Price R, Wei M, Yan W, Nowicki MO, Yoonhee P, Bergin SM, Hwang C, Kauer B, Caligiuri MA, Chiocca EA. The HDAC inhibitor valproic acid lessens NK cell action against oncolytic virus-infected glioblastoma cells with inhibition of STAT5/T-BET signaling and IFNγ generation. Journal of Virology

7 AWARDS AND HONORS 2016 Research Day Travel Award, OSU 2013 P4 Summer Scholars Programs 2013 Medical Scientist Training Program Leadership and Academic Achievement Award, OSU 2012 Medical Scientist Training Program Leadership and Academic Achievement Award, OSU 2012 Patient Ethics Essay Award, Office of Research Education, OSU FUTURE PLANS Stephen Bergin will return to medical school to complete his medical training, after which he will pursue a research residency.

8 [This must be the first line on Page 8] Biomedical Sciences Graduate Program 1170 Graves Hall 333 W. 10 th Avenue Columbus, Ohio