A New Intervention to Control Inflammation in Alzheimer’s Disease

Yuxiang Sun, PhD
Texas AgriLife (Texas A&M University) (College Station, TX)
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2022
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2019630S
Award Type:
Standard
Award Region:
US Southern
yuxiang-sun

Ghrelin Receptor Mediated Neuroinflammation in Alzheimer’s Disease

Summary

Low-grade chronic inflammation is a hallmark of aging, and inflammation in the brain causes and worsens Alzheimer’s Disease (AD). We have evidence that suppression of a gene called GHS-R in immune cells produces an anti-inflammatory effect in the brain and improves spatial memory.  The goal of this proposal is to determine the role of GHS-R in immune cells in AD. This has potential to lead to novel interventions for combating AD by suppressing inflammation.

Details

Alzheimer’s disease (AD) is a devastating neurodegenerative disease with no effective treatment. Emerging evidences suggest that neuroinflammation has a major role in the pathogenesis of AD. Neuroinflammation is mediated by myeloid cells in the brain, which consist of resident microglia and infiltrating monocyte-derived macrophages (mo-Mf) recruited from circulation upon stress/injury.  Similar to peripheral macrophages, microglia and mo-Mf cells are highly plastic and dynamic, shifting from resting state to activated state in response to environmental insults. Activated pro-inflammatory microglia/mo-Mf cells produce pro-inflammatory cytokines that elicit neuropathology. Understanding the activation and polarization of microglia and mo-Mf is of great importance in combating neuroinflammation in AD. Ghrelin receptor, growth hormone secretagogue receptor (GHS-R), is an important nutrient sensor and metabolic regulator. We showed that GHS-R is abundantly expressed in macrophages; its expression in macrophages increases during aging and under high fat diet (HFD) feeding. We have reported that global ablation of GHS-R mitigates systemic inflammation in aging, showing anti-inflammatory macrophage polarization. To study the specific effect of GHS-R in myeloid cells, we generated myeloid-specific GHS-R deficient mice (LysM-Cre;Ghsrflox/flox). We will carry out the following specific studies: 1. Determine the effects of myeloid GHS-R deficiency on neuroinflammation and AD pathology. 2. Determine the molecular signatures and regulatory mechanisms of GHS-R deficient microglia/mo-Mf cells.  We anticipate that novel immunotherapy of targeting GHS-R in myeloid cells likely have potential to reprogram myeloid cells in the brain to combat AD.

About the Researcher

Dr. Yuxiang Sun is an associate professor in the Department of Nutrition and Food Science at Texas A&M University (TAMU). She received her M.D. from Beijing Medical University in China, and her Ph.D. from the University of Manitoba in Canada. She subsequently pursued postdoctoral training and started her independent career at Baylor College of Medicine. She joined the Department of Nutrition & Food Science at TAMU in December 2015.

Dr. Sun’s research interests include nutritional regulation, obesity, diabetes, immunometabolism, and “inflamm-aging”. Dr. Sun’s career has largely revolved around gut hormone ghrelin, which is a very important nutrient sensor and metabolic regulator. She generated the first set of global knockout mice for ghrelin and the ghrelin receptor, and discovered ghrelin’s novel functions in diabetes, thermogenesis, and macrophage polarization. Her laboratory has generated a series of tissue-specific ghrelin receptor knockout mice. Her team uses these state-of-the-art tools to study the sites of action and cellular/molecular mechanisms of ghrelin signaling using integrative physiology, neuroendocrinology, and biochemical and immunological approaches. The ongoing projects in her lab aim to investigate the roles of ghrelin signaling in: 1) Energy- and glucose-hemostasis; 2) Macrophage-mediated adipose tissue inflammation and nonalcoholic steatohepatitis; 3) Neuro-inflammation and neurodegenerative diseases such as Alzheimer’s disease. 

Dr. Sun has over 80 peer-reviewed publications with an H index of 31. These include articles in premier journals such as Cell Metabolism, PNAS, JCI, Aging Cell, Aging, Diabetes, Nature Communications, etc. The findings reported in these publications suggest that ghrelin signaling is a very promising drug target for obesity, diabetes, inflammation, and neurodegenerative diseases. Dr. Sun is a renowned expert in the ghrelin field and is a well-recognized investigator in the field of aging. Her long-term goal is to develop therapeutic strategies to prevent/treat chronic diseases, with the ultimate objectives of improving health, vitality and longevity in humans.

Personal Story

Aging and age-related diseases have been my passion throughout my career. I did my postdoctoral training in aging because I was inspired to find the “Fountain of Youth”. Along the way, I have come to realize that quality of life – “healthspan” – is even more crucial for the elderly than longevity. People not only want to live longer, but most importantly they want to live healthier. When I started my own laboratory, I decided to focus my research on “healthspan” and age-related diseases. In order to pass on my passion to the next generation, when I joined TAMU I have built a graduate course named “Nutrition and Healthy Aging”. Chronic inflammation is a hallmark of aging, and concomitantly causes/promotes many age-related diseases and accelerates aging. Thus, the current primary focus of my lab is inflamm-aging in neurodegenerative diseases such as Alzheimer’s disease. There is no better feeling in the world than to get up every day to do the things I am passionate about. I feel so blessed. I am enormously grateful to the donors of BrightFocus. Your generosity enables me to make the discoveries that give meaning to my life. I promise you I will do my very best to use your support wisely to generate most impact findings, and to inspire and educate new generations of researchers.

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