Research Pillar: Clinical

Integrative genomics to identify novel therapeutics and biomarkers for COPD

Chronic obstructive pulmonary disease (COPD) affects 300 million people worldwide and is the third leading cause of death, responsible for over 3 million deaths per year. It is the number one reason why adults end up in hospitals. However, we do not have good drugs to treat patients with COPD. This is because we do not fully understand how and why COPD develops and progresses.

Smoking can cause COPD but not all smokers get the disease; our genes also play a role. Identifying which genes cause some people to get COPD or lead to disease worsening over time will allow us to understand these processes more and to develop new drugs to treat the disease.

This project will use sophisticated analysis tools called integrative genomics. First, we will identify regions of our DNA that are important for COPD risk and worsening over time. This will be done through studying DNA regions from thousands of subjects with and without the disease and on whom we have information on how well their lungs work. We will then identify the function of these DNA regions by uncovering their effect on gene products and proteins in tissues that are important and relevant for COPD such as lung and blood. These genes and their products will be tested in laboratories to confirm the findings. The goal is to use this information to monitor disease and will additionally allow us to interfere with these gene products to treat disease.

Imaging repair: Developing and applying unconventional neuroimaging methods for quantitative assessment of tissue health

Magnetic resonance imaging (MRI) is a powerful tool for measuring changes in the brain and spinal cord that occur over the course of neurological disease. Unfortunately, conventional MRI is qualitative, so the biological cause of the changes seen on MRI is difficult to determine.

Damage to myelin, the substance that surrounds the nerve fibres (axons) of the brain and spinal cord to speed up signal transmission and protect the axons themselves, is a common feature for many neurological diseases. While myelin can be repaired, axonal damage is irreversible.

Dr. Kolind is focused on developing and applying advanced MRI techniques that provide measures related to myelin loss or axonal damage. The greater sensitivity and specificity afforded by these advancements provides critical information regarding the underlying processes in neurological disease. This insight is needed to understand such diseases and target treatment development. Further, the quantitative nature of these techniques may dramatically reduce the number of patients and time period required for successful demonstration of new therapies. This approach has tremendous potential for clinical trials and research studies in countless neurological diseases and injuries.

Sexual pain in endometriosis: Role of somatic mutations

Endometriosis is a common condition, affecting 1 in 10 women of reproductive age, or approximately one million women in Canada. Endometriosis occurs when tissue from inside the womb grows outside of the womb, such as in different areas of the pelvis. Half of women with endometriosis experience sexual pain, which is felt as pelvic pain with deep penetration during sexual activity. 

Sexual pain in endometriosis can occur when the endometriosis cells show invasive qualities. We recently identified non-inherited gene mutations in this type of invasive endometriosis. 

Our team has established a registry of endometriosis patients along with surgical samples from these patients. I will validate the role of gene mutations in endometriosis sexual pain, in particular whether these mutations are associated with invasion of endometriosis, and also with increased nerve growth around endometriosis. 

In the future, gene mutation testing could be incorporated into clinical care for endometriosis to identify subgroups and promote more individualized care. These mutations could also be potential novel treatment targets for this common condition in women.

Assessment of breast cancer and response to systemic therapy before surgery using diffuse optical imaging technology

Breast cancer is the most common cancer in women. Patients with large breast tumour or palpable lymph nodes often receive chemotherapy first, followed by surgery. During chemotherapy, a doctor performs serial breast exams and occasional imaging to monitor tumour shrinkage, but this is not good enough to capture shrinkage accurately. It is important to develop a better way to measure breast cancer response on chemotherapy before surgery, as it can predict outcomes and change treatment plans.

Diffuse Optical Imaging (DOI) takes advantage of different light scatter properties in different biological tissues (for example, normal tissue, cavities, cancer and blood have different scatter properties in infrared spectrum). Our team has developed a hand-held DOI-Scan probe (optical probe) which has shown promising preliminary findings in patients without prior diagnosis of breast cancer. 

We will use this real-time, easy-to-use, point-of-care imaging tool to examine normal breast and breast tumour characteristics in patients with locally advanced early breast cancer prior to and after each cycle of systemic therapy, alongside serial breast examinations and ultrasound imaging, to see how breast cancer appears and responds to chemotherapy given before curative surgery. The results will be compared with the final surgical specimen and patient outcomes.

Cerebral Oximetry to assess CErebral autoregulation in Hypoxemic Ischemic Brain Injury (COnCEpT – HIBI)

There are 40,000 patients who suffer a cardiac arrest in Canada each year. When the heart stops beating from a cardiac arrest, blood flow to the brain stops which can lead to large strokes, called ischemic brain injury. Only a small percentage of people who develop ischemic brain injury survive with normal brain function.  

The overall goal of this research is to improve the neurologic outcomes of critically ill patients who have suffered a severe brain injury after cardiac arrest by determining how to personalize blood pressure targets for individual patients to ensure adequate cerebral blood flow (CBF). CBF in the first few millimetres of brain tissue can be measured non-invasively by near-infrared spectroscopy (NIRS), using sensors applied to the forehead. I have previously demonstrated that we can use the NIRS to determine the patient-specific blood pressure, but it is unclear if maintaining this individualized blood pressure leads to better outcomes.

To address this gap, my Heart & Stroke Foundation funded study will enroll 60 patients in 3 intensive care units across Canada following cardiac arrest. The objective is to determine the association between the amount of time spent at the patients individualized blood pressure threshold, and neurologic outcomes at 6-months. The results of this study will be used to design a large interventional study of individualized blood pressure management and neurologic outcomes.

Improving outcomes in the treatment of eating disorders: Self-compassion in patients, families and clinicians

Self-compassion refers to an individual's capacity to be mindful, recognize our common humanity in times of hardship, and to practice self-kindness in times of suffering. It has been shown to be beneficial in working with individuals with chronic health conditions, such as HIV/AIDS, diabetes, and eating disorders. However, many individuals have difficulty with this skill and experience barriers to being self-compassionate. 

This research will help us understand how self-compassion can benefit individuals with chronic health conditions. We will interview patients in treatment, recovered patients, and clinicians about their experiences with self-compassion. Their responses will be used to design an intervention that aims to increase capacity of individuals with chronic health conditions to benefit from self-compassion. We will also explore self-compassion in family members and clinicians to increase understanding of what gets in the way of a collaborative stance, shown to be most helpful to individuals with chronic health conditions. We will share results of this research with clinicians, patients and families locally at education days and provincial video conferences, and nationally and internationally through workshops, conference presentations and publications.

IgE-mediated inflammation generated by the airway epithelium is antigen independent: A cause of a novel asthma phenotype

Asthma is the most common chronic disease in childhood and continues to increase through adulthood. When a patient has asthma, airways in the lungs become swollen and tight causing symptoms such as shortness of breath, wheezing, chest tightness, and cough. Current therapies for asthma relieve symptoms but do not restore airways back to normal function or cure the disease.

Asthma is influenced by many different genetic and environmental factors, so despite having many drugs available and more in development it is extremely difficult to match patients to the right treatment. To better match patients to the right therapies we need to understand the process by which allergies lead to asthma.

This project aims to find new ways to predict the response of asthmatic patients to existing and new drugs by better understanding how allergies cause asthma symptoms. We will look at several molecules in the blood known to be important in asthma, and measure them in airway tissues and cells obtained from asthmatic and non-asthmatic patients. This will give us a much better picture of what these important molecules are doing directly at the source of the allergic inflammation.

The effects of balance training with or without cognitive training in older adults with MCI and impaired mobility

Mild cognitive impairment (MCI) is an intermediate stage between normal cognitive function and dementia. The rate of progression of MCI to dementia in older adults has been found to be between 10-12% per year, whereas those without cognitive impairment acquire dementia at a rate of only 1-2% per year. MCI has been linked to poor dual-tasking, impaired balance and functional mobility, and is a significant risk factor for falls. Individuals with MCI need preventive therapies that target both the cognitive and mobility-related outcomes. Dr. Jehu has identified pairing targeted dual-tasking training with balance and mobility training as a promising  preventative therapy.

In recent research, balance and mobility training (BMT), and balance and mobility plus cognitive training (BMT+C) programs have been shown to improve dual-tasking and functional mobility in the healthy older adult population; however no previous interventions have targeted dual-task training in individuals with MCI. Dr. Jehu will extend this work to individuals with MCI in order to improve cognitive and mobility outcomes. The BMT and BMT+C interventions will determine whether individuals with MCI can reverse cognitive and functional declines and improve to healthy older adult norms.

The timed up & go (TUG) is a commonly used clinical functional mobility assessment tool. TUG has been shown to be an independent predictor of cognitive decline following an ischemic stroke, and has accurately differentiated between healthy older adults and older adults with MCI. Dr. Jehu aims to use TUG to improve the diagnostic interpretation of important clinical measures used to evaluate individuals with MCI.

Dr. Jehu’s research may serve to improve the interpretation of clinical diagnostic tools, which could revolutionize the prescription of exercise in older adults with MCI and improve the overall interpretation of commonly used clinical assessment tools.

End of Award Update: April 2022

Most exciting outputs

In our study Sex differences in subsequent falls and falls-risk: A prospective cohort study in older adults (Gerontology, 2021), we found that modifiable risk factors related to cognition, physical function, psychological wellbeing, and health status predicted subsequent falls. In males, better mobility was not as protective of falls compared with females. This may be due to males’ poorer executive function, contributing to decreased judgement or slowed decision-making during mobility. These results may inform efficacious sex-specific falls prevention strategies.

Impacts so far

I would not have obtained a position as an assistant professor without my Health Research BC / Vancouver Coastal Health Research Institute Research fellowship. I am confident that the experience I had working with Dr. Teresa Liu-Ambrose provided me with the skills I needed to secure a job.

Potential future influence

During my fellowship, I learned the skills needed to become an independent researcher. Some skills include randomized controlled trial design, implementation science methods, how to conduct systematic reviews, skills in cognitive testing, grant writing, and working with patient populations such as older adults who fall and those with cognitive impairment

Next steps 

I am now an assistant professor at Augusta University in Augusta Georgia. I was recently awarded an intramural grant to examine the effects of 6 months of exercise on cognition among people living with dementia. I am thrilled to be leading a team of interdisciplinary researchers and healthcare professionals.

Useful links 

Improving whole-genome sequencing as a clinical test for intellectual disability

Intellectual disability (ID) is a life-long affliction that impairs the cognitive functioning and adaptive behavior of affected individuals. About two to three percent of people worldwide suffer from ID. ID is mostly caused by irregularities in the DNA of an individual and is the most common reason for genetic testing. There are thousands of different mutations that we now know can cause ID. Diagnosis is necessary for accurate and effective genetic counselling, however deciphering the underlying genetic component remains a challenge.

The emergence of next-generation sequencing technologies, notably whole-genome sequencing (WGS), has empowered the identification of genetic cause in more than half of all patients with severe ID. WGS allows scanning of the entire genome of an individual for abnormalities in DNA sequence. The number of accurate diagnoses are three to four times higher than what is achievable with current methods. The current major limitation is that WGS fails to detect certain types of mutations.

Dr. Rajan Babu’s research aims to improve the clinical effectiveness of WGS by expanding its detection abilities to include all ID-causing pathogenic mutations, including those that aren’t currently being identified. She will employ an advanced WGS technology and analyze the generated data using three well-optimized bioinformatics pipelines, enhancing the diagnostic sensitivity of WGS.

The results of this research will be incorporated in the standard clinical diagnostic evaluation of patients with ID to promote earlier and definitive diagnosis, and enable optimal clinical care and counselling of affected patients and their families. All patients with clinically actionable finding will be offered genetic counselling and consultation with appropriate medical specialists. Ultimately, Dr. Rajan Babu’s research could facilitate discovery of novel genetic aberrations and refine our understanding of the genes and the biological mechanisms involved in ID as well as reveal new potential targets for therapeutic intervention.

Exploring women’s experiences in a prediabetes community-based exercise intervention

Dr. Bean will explore women’s experiences throughout their participation in the Small Steps for Big Changes lifestyle counseling program, a community-based exercise intervention for individuals who are living with prediabetes. Interviews with participating women will provide an understanding of women’s attitudes, beliefs, experiences and behaviours related to engaging in a lifestyle community program, in order to best understand the facilitators and barriers to intervention engagement and completion, as well as exercise adherence over the course of one year. 

Women who have been diagnosed as prediabetic but do not have access to a community-based intervention will be interviewed in order to also understand these women’s attitudes, beliefs, experiences and behaviours over the course of the same year. This will help understand the influences and impacts of the intervention program, as well as understand if there is a need for more resources for these prediabetic women. 

Dr. Bean’s research will address several gaps in the current literature, including adopting a qualitative and longitudinal approach and attaining an in-depth understanding of the efficacy of community-based exercise interventions specifically for women. Her findings will be adapted into community learning sessions, which will provide an opportunity for a community of practice to develop for women involved in this study in which they can learn from each other’s experiences.