The influence of early life overweight on immune system development and asthma severity

Principle Investigator

Scientific interest within the context of the graduate college:

The most exciting phrase to hear in science, the one that heralds new discoveries, is not ‘Eureka!’ but ‘That’s funny…’   (Isaac Asimov)

We are a reproductive immunology group studying pregnancy, allergy, the gut microbiome and immune system development. Our research focuses on the “developmental origins of health and disease” hypothesis, which posits that perinatal environmental exposures (during the fetal and early neonatal life stages), can influence immunity and subsequent disease susceptibility later in life. Inappropriate nutritional inputs in early life can result in metabolic malprogramming of vital regulatory pathways which permanently alter the immune system, resulting hyperreactive inflammatory processes that persist for the lifetime of an individual.¹ As an example of this, childhood overweight and obesity present a serious public health concern, and are associated with an increased risk for non-communicable diseases such as asthma.² To address the increasing morbidity and mortality from non-communicable diseases, it is therefore crucial to understand the mechanisms that contribute to this phenomenon. The aim of this proposal is to use a mouse model to understand how overweight during infancy alters developmentally programmed inflammatory responses, as well as pathophysiological effects in the lung, with a focus on allergic asthma. The knowledge generated from this work will contribute to our understanding of how early onset metabolic derangements such as overweight, contribute to pathogenic changes in postnatally developing organ systems. This approach will identify potential pathways and windows of opportunity whereby we can counteract pathogenic developmental processes.

Project description:

Introduction: For your project, you will use our established mouse model of PostNatal OverFeeding (PNOF), in which mouse litters that are culled at 4 days of age encounter increased milk availability and excess calorie intake, and thus become overweight during infancy (an effect that persists into adulthood). We have previously shown with this model that PNOF mice have increased asthma severity, and your project will delve into the mechanism of why this is occurring. To do this your project will involve the following aims:

Aim 1: Characterize of how litter culling affects breast milk nutritional composition, as well as offspring body composition and serum parameters.

Aim 2: Assess the effect of early life overweight on the gut microbiome using metagenomic sequencing of fecal samples.

Aim 3: Understand how early life overweight affects immune system development and by performing 18-color flow cytometry in various organs.

To accomplish this, you will be trained in all aspects of mouse handling and reproductive strategies in our PNOF model, and also receive training in induction of experimental allergic asthma and analysis of the asthma phenotype. In addition to learning animal work and basic molecular biology techniques in the laboratory, your project will include major methods, such as gut microbiome metagenomic sequencing and 18-color flow cytometry immunophenotyping of different tissues.

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