Results of MI4 Pfizer Early Career Investigator Award

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Results of MI4 Pfizer Early Career Investigator Award

Winners

Year 3
Year 2
Year 1

听

Year 3

MI4 is pleased to award funding for three investigators in the final round of the MI4 Pfizer Early Career Investigator Award program. MI4 would like to acknowledge that support for this program has been provided by Pfizer Canada Inc.

Please join us in congratulating the following researchers on their successful submissions!

Lead Investigator	MI4 Pfizer Early Career Investigator Award
Sara Mahshid PhD (不良研究所)	Leveraging additive manufacturing and machine learning for rapid multiplexed phenotypic antibiotic susceptibility testing Lay Summary Antimicrobial resistance (AMR) is a major global health threat and among top research priorities. Antibiotic overuse is a major driver of AMR in human infections. Antibiotic-resistant bacteria are directly responsible for ~1.3 million annual deaths and are associated with nearly 5 million annual deaths globally. The overuse of antibiotics and the prescription of antibiotics to which bacteria are not susceptible, contribute to the rise of antibiotic resistance. This proposal aims to develop an ultrasensitive multiplexing approach for rapid phenotypic antibiotic susceptibility testing (AST), with versatile functionality for a broad range of human samples. The proposed diagnostic platform combines unique technological innovations from the Mahshid lab (high sensitivity colorimetric detector, microfluidic design, custom image acquisition, and machine learning), with well-validated phenotypic AST readouts (bacterial viability-based assay). The colorimetric detector is based on a novel plasmonic nanostructured material that can provide an ultrasensitive optical readout during the conversion of resazurin to resorufin 鈭� an indicator for bacterial viability and growth during antibiotic exposure.
Bryan Ross MD (MUHC)	From 鈥楿nderstanding鈥� to 鈥楶redicting鈥� Exacerbations: The COPD Remote Patient Monitoring Pandemic Platform Lay Summary Chronic obstructive pulmonary disease (COPD) is a common lung disease which carries a heavy burden both for patients and health systems. COPD is now the third-leading cause of death. 鈥楲ung attack鈥� episodes, called exacerbations, are a top cause of hospital admissions amongst all adult chronic illnesses. The ability to monitor patients with COPD and keep them well-managed and out of hospital is particularly important during pandemic situations, and yet lockdowns, social distancing, and pulmonary function lab closures make it even harder to provide effective chronic care. With recent advances in technology, 鈥榳earable鈥� biosensor devices can now be worn comfortably by outpatients with COPD and collect vital sign, activity, and sleep information near-continuously. Moreover, the newest COPD guidelines recommend using cut-offs in vital signs such as respiratory rate, heart rate and oxygen saturation to define and classify exacerbations.听Building off our research demonstrating the collection of near-continuous (multi-week) high-quality vital sign data remotely using 鈥榳earables鈥�, we now propose a COPD study whereby 鈥榟igh-risk鈥� patients for frequent exacerbations are provided with wearable wristbands/rings and a remote handheld oscillometer for daily lung function tests. Data leading up to each exacerbation event will be used to develop a powerful 鈥榩andemic-proof鈥� COPD remote monitoring platform.
Caroline Wagner PhD (不良研究所)	How do respiratory pathogens shape disease transmission through droplet formation? Lay Summary Respiratory viruses have been identified as having elevated pandemic potential, and generate a substantial infection burden globally. The dominant transmission modes of these viruses, i.e. by droplets, aerosols, or direct contact, strongly determines the effectiveness of different nonpharmaceutical interventions that may be put in place in both pandemic and epidemic contexts. Yet, very little is known about the biophysics of the processes of droplet generation and viral entrainment during transmission events between hosts, and, in particular, about how the presence of viruses themselves may impact these phenomena. Here, we propose studying this using a simplified system of nanoparticles (NPs) with tunable surface biochemistries, and gels of various biological polymers including mucins, the primary solid component of saliva and respiratory mucus. Specifically, our project aims include experimentally investigating the impact of NPs on the rheology and interfacial properties of biological gels, visualizing and recording the effect of NPs on the fragmentation of these gels following spraying events, and developing theory to relate the rheological and fragmentation results. The project team combines leading experts in mucosal biology, rheology, fluid mechanics, nanoparticle engineering, drug delivery, and disease modeling, and will support the training of graduate and undergraduate students, as well as research assistants.

Lead Investigator

MI4 Pfizer Early Career Investigator Award

Sara Mahshid

PhD (不良研究所)

Leveraging additive manufacturing and machine learning for rapid multiplexed phenotypic antibiotic susceptibility testing

Lay Summary

Antimicrobial resistance (AMR) is a major global health threat and among top research priorities. Antibiotic overuse is a major driver of AMR in human infections. Antibiotic-resistant bacteria are directly responsible for ~1.3 million annual deaths and are associated with nearly 5 million annual deaths globally. The overuse of antibiotics and the prescription of antibiotics to which bacteria are not susceptible, contribute to the rise of antibiotic resistance. This proposal aims to develop an ultrasensitive multiplexing approach for rapid phenotypic antibiotic susceptibility testing (AST), with versatile functionality for a broad range of human samples. The proposed diagnostic platform combines unique technological innovations from the Mahshid lab (high sensitivity colorimetric detector, microfluidic design, custom image acquisition, and machine learning), with well-validated phenotypic AST readouts (bacterial viability-based assay). The colorimetric detector is based on a novel plasmonic nanostructured material that can provide an ultrasensitive optical readout during the conversion of resazurin to resorufin 鈭� an indicator for bacterial viability and growth during antibiotic exposure.

Bryan Ross

MD (MUHC)

From 鈥楿nderstanding鈥� to 鈥楶redicting鈥� Exacerbations: The COPD Remote Patient Monitoring Pandemic Platform

Lay Summary

Chronic obstructive pulmonary disease (COPD) is a common lung disease which carries a heavy burden both for patients and health systems. COPD is now the third-leading cause of death. 鈥楲ung attack鈥� episodes, called exacerbations, are a top cause of hospital admissions amongst all adult chronic illnesses. The ability to monitor patients with COPD and keep them well-managed and out of hospital is particularly important during pandemic situations, and yet lockdowns, social distancing, and pulmonary function lab closures make it even harder to provide effective chronic care.

With recent advances in technology, 鈥榳earable鈥� biosensor devices can now be worn comfortably by outpatients with COPD and collect vital sign, activity, and sleep information near-continuously. Moreover, the newest COPD guidelines recommend using cut-offs in vital signs such as respiratory rate, heart rate and oxygen saturation to define and classify exacerbations.听Building off our research demonstrating the collection of near-continuous (multi-week) high-quality vital sign data remotely using 鈥榳earables鈥�, we now propose a COPD study whereby 鈥榟igh-risk鈥� patients for frequent exacerbations are provided with wearable wristbands/rings and a remote handheld oscillometer for daily lung function tests. Data leading up to each exacerbation event will be used to develop a powerful 鈥榩andemic-proof鈥� COPD remote monitoring platform.

Caroline Wagner

PhD (不良研究所)

How do respiratory pathogens shape disease transmission through droplet formation?

Lay Summary

Respiratory viruses have been identified as having elevated pandemic potential, and generate a substantial infection burden globally. The dominant transmission modes of these viruses, i.e. by droplets, aerosols, or direct contact, strongly determines the effectiveness of different nonpharmaceutical interventions that may be put in place in both pandemic and epidemic contexts. Yet, very little is known about the biophysics of the processes of droplet generation and viral entrainment during transmission events between hosts, and, in particular, about how the presence of viruses themselves may impact these phenomena.

Here, we propose studying this using a simplified system of nanoparticles (NPs) with tunable surface biochemistries, and gels of various biological polymers including mucins, the primary solid component of saliva and respiratory mucus. Specifically, our project aims include experimentally investigating the impact of NPs on the rheology and interfacial properties of biological gels, visualizing and recording the effect of NPs on the fragmentation of these gels following spraying events, and developing theory to relate the rheological and fragmentation results. The project team combines leading experts in mucosal biology, rheology, fluid mechanics, nanoparticle engineering, drug delivery, and disease modeling, and will support the training of graduate and undergraduate students, as well as research assistants.

Year 2

MI4 is pleased to award funding for two investigators in Year 2 of the MI4 Pfizer Early Career Investigator Award program. MI4 would like to acknowledge that support for this program has been provided by Pfizer Canada Inc.

MI4 is also delighted to announce that they have partnered with the 不良研究所 Faculty of Medicine and Health Sciences to support an additional project, with a gift from the Charles O. Monat Foundation, for the FMHS-MI4 Early Career Investigator Award.

Please join us in congratulating the following researchers on their successful submissions!

Lead Investigator	MI4 Pfizer Early Career Investigator Award
Qian Liu PhD (不良研究所)	Single-molecule interactions between Nipah virus and the interferon-induced transmembrane proteins Lay Summary Viral infections pose a great threat to public health and the global economy. The majority are caused by emerging viruses that originated from animals and infect humans. It is urgent to develop intervention strategies against emerging viral diseases. We need to understand the fundamental mechanisms of how viruses infect cells and how the cell's innate immune defenses against the novel viral infections. Nipah virus (NiV) is an emerging paramyxovirus with the capability of human-human and animal-human transmissions and has a mortality rate of 40-70%. It is listed in the WHO blueprint priority diseases for research and development because of its epidemic potential and lack of countermeasures. Like other Enveloped viruses, NiV enters cells via the fusion between the virus and cell membranes. The interferon-induced transmembrane proteins (IFITMs) restrict the entry of unrelated viruses by modulating the biophysical properties of the membrane. Here, by using a combination of single-molecule imaging, mutagenesis, and biochemistry tools, we will probe how IFITMs restrict the entry and transmission of the NiV on a nanoscale. The precise information on the nano organization of viral and host factors will provide new insights into the subtle mechanisms of NiV infection and IFITMs鈥� antiviral activities.
Laurence Chapuy MD, PhD (MUHC)	Plasticity of human monocytes towards regulatory macrophages in Crohn's disease Lay Summary Inflammatory bowel disease (IBD), including Crohn's disease (CD), affects 300,000 Canadians. IBD is caused by an abnormal immune response resulting in chronic intestinal inflammation that can lead to gut scarring, called fibrosis. This scarring results in a narrowing of the intestine that may require one or more surgeries during the course of the disease. Dr. Chapuy's research program focuses on the role of immune cells called monocytes and macrophages in developing intestinal fibrosis. When blood monocytes enter the intestine, they transform into macrophages, which will promote inflammation, tissue repair, or fibrosis, depending on the context. This ability of monocytes to adapt to the environment is called cell plasticity. We study the characteristics of monocytes and macrophages in the fibrotic intestine of CD patients who underwent surgery. Using state-of-the-art technologies, we analyze surgical specimens to define the nature and function of different cell types present in the scarred and adjacent healthy areas. By comparing them, we can deduce if and how the different types of monocytes and macrophages in the intestine promote fibrosis. The project aims to develop drugs to treat or prevent complications in CD patients and improve long-term outcomes and quality of life.

Lead Investigator

MI4 Pfizer Early Career Investigator Award

Qian Liu

PhD (不良研究所)

Single-molecule interactions between Nipah virus and the interferon-induced transmembrane proteins

Lay Summary

Viral infections pose a great threat to public health and the global economy. The majority are caused by emerging viruses that originated from animals and infect humans. It is urgent to develop intervention strategies against emerging viral diseases. We need to understand the fundamental mechanisms of how viruses infect cells and how the cell's innate immune defenses against the novel viral infections. Nipah virus (NiV) is an emerging paramyxovirus with the capability of human-human and animal-human transmissions and has a mortality rate of 40-70%. It is listed in the WHO blueprint priority diseases for research and development because of its epidemic potential and lack of countermeasures. Like other Enveloped viruses, NiV enters cells via the fusion between the virus and cell membranes. The interferon-induced transmembrane proteins (IFITMs) restrict the entry of unrelated viruses by modulating the biophysical properties of the membrane. Here, by using a combination of single-molecule imaging, mutagenesis, and biochemistry tools, we will probe how IFITMs restrict the entry and transmission of the NiV on a nanoscale. The precise information on the nano organization of viral and host factors will provide new insights into the subtle mechanisms of NiV infection and IFITMs鈥� antiviral activities.

Laurence Chapuy

MD, PhD (MUHC)

Plasticity of human monocytes towards regulatory macrophages in Crohn's disease

Lay Summary

Inflammatory bowel disease (IBD), including Crohn's disease (CD), affects 300,000 Canadians. IBD is caused by an abnormal immune response resulting in chronic intestinal inflammation that can lead to gut scarring, called fibrosis. This scarring results in a narrowing of the intestine that may require one or more surgeries during the course of the disease. Dr. Chapuy's research program focuses on the role of immune cells called monocytes and macrophages in developing intestinal fibrosis. When blood monocytes enter the intestine, they transform into macrophages, which will promote inflammation, tissue repair, or fibrosis, depending on the context. This ability of monocytes to adapt to the environment is called cell plasticity. We study the characteristics of monocytes and macrophages in the fibrotic intestine of CD patients who underwent surgery. Using state-of-the-art technologies, we analyze surgical specimens to define the nature and function of different cell types present in the scarred and adjacent healthy areas. By comparing them, we can deduce if and how the different types of monocytes and macrophages in the intestine promote fibrosis. The project aims to develop drugs to treat or prevent complications in CD patients and improve long-term outcomes and quality of life.

Lead Investigator	FMHS-MI4 Early Career Investigator Award, with a gift from the Charles O. Monat Foundation听
Ajitha Thanabalasuriar PhD (不良研究所)	Deciphering the mechanism of e-cigarette mediate development of lung disease Lay Summary Electronic cigarettes (e-cigs) were originally introduced to help adults stop smoking tobacco. However, the use of sweet and fruity flavours has resulted in e-cigs becoming increasingly popular among teenagers (12-18 years old). Teens that have been using e-cigs for less than one year have been reported to develop rapid and life-threatening lung disease. Lung disease seen in e-cig using teenagers include lung injury and pneumonia. Improper immune responses to lung infections, ranging from scarce to excess immune cells moving into the lung, can result in disease. We have developed a mouse model of e-cig vape usage with one of the most popular ecig vape flavours (berry mix) and devices among teenage users. Using this model, we have found that e-cig vape containing a berry flavor decreases the important infection fighting immune cell, neutrophils, in the body. In this proposal we will understand what causes this change in neutrophil numbers and how e-cig exposed animals respond to infection. Moreover, we will look at human e-cig users to see if they have similar changes in neutrophils in their blood. Together we aim to understand and prevent lung disease after e-cig use.

Lead Investigator

FMHS-MI4 Early Career Investigator Award, with a gift from the Charles O. Monat Foundation听

Ajitha Thanabalasuriar

PhD (不良研究所)

Deciphering the mechanism of e-cigarette mediate development of lung disease

Lay Summary

Electronic cigarettes (e-cigs) were originally introduced to help adults stop smoking tobacco. However, the use of sweet and fruity flavours has resulted in e-cigs becoming increasingly popular among teenagers (12-18 years old). Teens that have been using e-cigs for less than one year have been reported to develop rapid and life-threatening lung disease. Lung disease seen in e-cig using teenagers include lung injury and pneumonia. Improper immune responses to lung infections, ranging from scarce to excess immune cells moving into the lung, can result in disease. We have developed a mouse model of e-cig vape usage with one of the most popular ecig vape flavours (berry mix) and devices among teenage users. Using this model, we have found that e-cig vape containing a berry flavor decreases the important infection fighting immune cell, neutrophils, in the body. In this proposal we will understand what causes this change in neutrophil numbers and how e-cig exposed animals respond to infection. Moreover, we will look at human e-cig users to see if they have similar changes in neutrophils in their blood. Together we aim to understand and prevent lung disease after e-cig use.

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Year 1

MI4 is pleased to award funding for two investigators in Year 1 of the MI4 Pfizer Early Career Investigator Award program. MI4 would like to acknowledge that support for this program has been provided by Pfizer Canada Inc.

MI4 is also delighted to announce that they have partnered with the Lady Davis Institute (LDI) and Jewish General Hospital (JGH) Foundation to support an additional project for the LDI-JGH MI4 Early Career Investigator Award. Congratulations to all the awardees!

Please join us in congratulating the following researchers on their successful submissions!

Lead Investigator	MI4 Pfizer Early Career Investigator Award
Ian Watson PhD (不良研究所)	Investigation of sex differences in response to immune checkpoint inhibitors in melanoma Lay Summary More men develop melanoma than women. Once male patients have melanoma, they have a worse prognosis than female patients. In the past, this has been attributed to differences in behavior. However, evidence now clearly points to biological sex differences being responsible for this phenomenon. Furthermore, reports are emerging that male and female patients have different drug responses to the latest melanoma treatments. Interestingly, reports indicate men have better responses to immune therapies and women respond better to targeted therapies. The reason for this is unknown. Our group recently identified a gene that is preferentially mutated in male melanoma patients. We believe mutations in this gene may explain the observed sex differences in patient response to immune therapies, which we will investigate in this this study. Our research will lead to a better understanding of the differences in the biology of melanomas between male and female patients. Importantly, our study will work towards developing clinical tests that may help select patients most likely to benefit from either immune or targeted therapies.
Abhinav Sharma MD (MUHC)	Optimizing the timing of influenza vaccination in patients with heart failure: the FLU-HF randomized trial Lay Summary Heart failure (HF) is one of the most common causes of hospital admission in Canada and costs the Canadian healthcare system over $1 billion annually. Influenza vaccination is an inexpensive strategy to prevent influenza infections and reduce an important trigger for HF decompensation and hospital readmission. Yet, the optimal timing of vaccine administration remains unclear. When patients with HF are admitted to the hospital with an acute decompensation in advance of, or during, the 鈥榝lu season鈥�, this can be an ideal time to administer the vaccine. However, patients with acute HF decompensation have significant inflammatory injury, and may have substantially impaired immune responses; thus vaccine administration while admitted during an acute decompensated HF episode may not lead to high anti-influenza antibody titres. A more effective strategy can be to vaccinate after the decompensation has resolved, when patients are more stable. The FLU-HF randomized trial will determine whether administering the influenza vaccine to patients admitted in-hospital with an acute HF decompensation or waiting until they have stabilized as an out-patient leads to an improved anti-influenza response. We hypothesize that the seasonal influenza vaccination given to patients acutely decompensated with HF will elicit diminished humoral immune response (seroresponse) compared to patients receiving vaccination when stabilized as an out-patient. The primary outcome will be the number of individuals who develop protective antibodies to influenza virus strains included in the vaccine. This study will significantly inform a larger multicentre trial evaluating clinical outcomes.

Lead Investigator

MI4 Pfizer Early Career Investigator Award

Ian Watson

PhD (不良研究所)

Investigation of sex differences in response to immune checkpoint inhibitors in melanoma

Lay Summary

More men develop melanoma than women. Once male patients have melanoma, they have a worse prognosis than female patients. In the past, this has been attributed to differences in behavior. However, evidence now clearly points to biological sex differences being responsible for this phenomenon. Furthermore, reports are emerging that male and female patients have different drug responses to the latest melanoma treatments. Interestingly, reports indicate men have better responses to immune therapies and women respond better to targeted therapies. The reason for this is unknown.

Our group recently identified a gene that is preferentially mutated in male melanoma patients. We believe mutations in this gene may explain the observed sex differences in patient response to immune therapies, which we will investigate in this this study. Our research will lead to a better understanding of the differences in the biology of melanomas between male and female patients. Importantly, our study will work towards developing clinical tests that may help select patients most likely to benefit from either immune or targeted therapies.

Abhinav Sharma

MD (MUHC)

Optimizing the timing of influenza vaccination in patients with heart failure: the FLU-HF randomized trial

Lay Summary

Heart failure (HF) is one of the most common causes of hospital admission in Canada and costs the Canadian healthcare system over $1 billion annually. Influenza vaccination is an inexpensive strategy to prevent influenza infections and reduce an important trigger for HF decompensation and hospital readmission. Yet, the optimal timing of vaccine administration remains unclear. When patients with HF are admitted to the hospital with an acute decompensation in advance of, or during, the 鈥榝lu season鈥�, this can be an ideal time to administer the vaccine. However, patients with acute HF decompensation have significant inflammatory injury, and may have substantially impaired immune responses; thus vaccine administration while admitted during an acute decompensated HF episode may not lead to high anti-influenza antibody titres. A more effective strategy can be to vaccinate after the decompensation has resolved, when patients are more stable. The FLU-HF randomized trial will determine whether administering the influenza vaccine to patients admitted in-hospital with an acute HF decompensation or waiting until they have stabilized as an out-patient leads to an improved anti-influenza response. We hypothesize that the seasonal influenza vaccination given to patients acutely decompensated with HF will elicit diminished humoral immune response (seroresponse) compared to patients receiving vaccination when stabilized as an out-patient. The primary outcome will be the number of individuals who develop protective antibodies to influenza virus strains included in the vaccine. This study will significantly inform a larger multicentre trial evaluating clinical outcomes.

LEAD INVESTIGATOR	LDI-JGH MI4 EARLY CAREER INVESTIGATOR AWARD
Khashayar Esfahani MD (JGH)	Uncoupling the efficacy and toxicity of immune checkpoint inhibitors through the novel use of kinase inhibitors Lay Summary In the last decade, cancer care has made enormous strides forward with the development of treatments that activate our natural immune system to attack cancer cells. Specifically, drugs called 鈥淚mmune checkpoint inhibitors鈥� (ICIs) have provided dramatic improvements in response and overall survival to a growing number of deadly malignancies. Unfortunately, the activated immune system does not always exclusively target cancer cells. Indeed, inappropriate targeting of normal human tissues has led to a wide variety of auto-immune side effects, which can sometimes be severe and long-lasting, even occasionally fatal. We have studied how small molecules that inhibit intra-cellular signaling can modify the response to ICI in animal models, and more recently, in patients experiencing severe side effects. In this application, we propose to test whether such inhibitors can increase anti-tumor activity and/or decrease auto-immune toxicity in an animal cancer model where both anti-tumor activity and auto-immune toxicity are induced. Our focus will be on melanoma as the cancer model and immune colitis as the toxicity of interest. We anticipate this work to lead to the development of new treatments to combine with ICI to increase anti-cancer activity while decreasing or controlling immune side effects.

LEAD INVESTIGATOR

LDI-JGH MI4 EARLY CAREER INVESTIGATOR AWARD

Khashayar Esfahani

MD (JGH)

Uncoupling the efficacy and toxicity of immune checkpoint inhibitors through the novel use of kinase inhibitors

Lay Summary

In the last decade, cancer care has made enormous strides forward with the development of treatments that activate our natural immune system to attack cancer cells. Specifically, drugs called 鈥淚mmune checkpoint inhibitors鈥� (ICIs) have provided dramatic improvements in response and overall survival to a growing number of deadly malignancies. Unfortunately, the activated immune system does not always exclusively target cancer cells. Indeed, inappropriate targeting of normal human tissues has led to a wide variety of auto-immune side effects, which can sometimes be severe and long-lasting, even occasionally fatal.

We have studied how small molecules that inhibit intra-cellular signaling can modify the response to ICI in animal models, and more recently, in patients experiencing severe side effects. In this application, we propose to test whether such inhibitors can increase anti-tumor activity and/or decrease auto-immune toxicity in an animal cancer model where both anti-tumor activity and auto-immune toxicity are induced. Our focus will be on melanoma as the cancer model and immune colitis as the toxicity of interest. We anticipate this work to lead to the development of new treatments to combine with ICI to increase anti-cancer activity while decreasing or controlling immune side effects.

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不良研究所

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