Microbiome Influences Microglia Phenotypes and Aβ Amyloidosis in a Sex-specific Manner

Hemraj Dodiya, PhD
University of Chicago (Chicago, IL)

Mentors

Sangram S. Sisodia, PhD
University of Chicago (Chicago, IL)
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2021
Disease:
Alzheimer's Disease
Award Amount:
$200,000
Grant Reference ID:
A2019032F
Award Type:
Postdoctoral Fellowship
Award Region:
US Midwestern
HEMRAJ DODIYA

Microbiome Influences Microglia Phenotypes and Aβ Amyloidosis in a Sex-specific Manner

Summary

Alzheimer’s disease (AD) features brain deposition of amyloid-β protein, forming plaques, and inflammation leading to dementia. Emerging evidence suggests that men and women exhibit different gut microbiota which regulates the human immune system and influences their brain function. Series of experiments will assess the role of gender-specific microbes in regulating inflammation and amyloid-β deposition using mouse models of AD. Knowledge gained will advance our understanding of AD susceptibility in men and women linking how different gut microbes educates immune system affecting disease course, and identify novel potential therapeutic options to treat AD in men and women separately.

Details

Proposed series of studies focus on investigating the microbiota-brain axis in Alzheimer's pathogenesis using transgenic mouse models of Alzheimer's disease. I plan to investigate the cellular and molecular mechanism(s) by which the gut microbiome modulates brain immune function and amyloid-β pathology. Our previous reports demonstrate that the gut microbiome plays a vital role in Alzheimer's amyloid pathology and microglial function in a sex-specific manner. As a follow-up, aim 1 of my current proposal will investigate if antibiotic-treated female mice can confer the reduced amyloid pathology and altered microglia characteristics after fecal transfer from antibiotic-treated male mice. The second aim will examine if an altered microglial function due to changes in the gut microbiome is causing reduced amyloid pathology in male mice and no changes in female mice. The last aim focuses to investigate if Alzheimer's patients' microbiome is pathogenic compared to control subjects. The idea that sex-specific microbiome could be a driving factor for different susceptibilities in men and women is an innovative approach. Results from these series of studies will strengthen the role of the microbiota-brain axis in Alzheimer's disease and can shed light on the sexual dimorphism of Alzheimer's disease. Data generated from these studies will open doors for future therapeutic intervention studies aiming at the microbiota-brain axis in Alzheimer’s and other neurodegenerative conditions.

About the Researcher

My long-term research interest involves the development of a comprehensive understanding of the microbiota-gut-brain axis and its role in the pathogenesis of age-associated neurodegenerative disorders. My research experience and doctoral training have provided me with an excellent background in multiple biological disciplines including biotechnology, pharmacology, neuroscience, gastroenterology and molecular biology. My pre-doctoral work at Rush University includes both pre-clinical and clinical research. The majority of these studies were focused on gene therapy and stem cell based therapeutic interventions for neurodegenerative disorders such as Parkinson’s disease (PD), Huntington’s disease and Alzheimer’s disease (AD). During my doctoral training with Prof. Ali Keshavarzian (an active clinician and researcher in Gastroenterology) and Prof. Jeffrey H. Kordower (an internationally recognized Neuroscientist), my research focused on investigating a possible role of intestinal dysfunction in PD pathogenesis via gut-brain axis. During my post-doctoral training, I plan to evaluate the role of the microbiome-brain axis in AD, targeting molecular level mechanisms aiming to fulfill the knowledge gap in microbiome-immune interaction of Alzheimer’s pathogenesis under the mentorship of Prof. Sangram S. Sisodia (an internationally recognized expert in Alzheimer’s disease) at the U of Chicago. My choice of mentor, collaborators and research projects will give me a solid foundation to reach my short-term goal of studying the microbiota-brain axis in AD in a sex-specific manner. The expertise and proven track record that I present in the gut-brain axis field, alongside fruitful collaborations with multidisciplinary leaders and being immersed in an enabling scientific environment, allows me to successfully interrogate my proposed research studies and develop into a future independent faculty.

Personal Story

Alzheimer’s disease is the most common age-related chronic progressive neurodegenerative diseases with no current cure. The therapeutic approaches are focused solely on symptomatic relief to improve the quality of life for Alzheimer’s patients. Thus, there is a clear need for a better understanding of Alzheimer's disease to propose an effective prognosis, delay its progression and prevent it from its occurrence. In my proposed studies to the Bright Focus Foundation, we plan to investigate the microbiota-brain axis in Alzheimer's disease. I believe that under the mentorship of Prof. Sisodia, I will employ a unique and innovative microbiota-brain approach to improve our understanding of Alzheimer's disease. These results could answer the following critical questions: 1) can female Alzheimer's patients benefit from fecal transfer procedure from male control subjects? and 2) can we target the gut microbiome to enhance brain immune cells’ function to reduce Alzheimer’s amyloid pathology? Data generated from these studies will allow us to explore new therapeutic approaches targeting microbiota-brain axis in Alzheimer's disease.

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