The discovery that humans are able to regenerate new neurons through a process called neurogenesis has transformed our understanding of the brain’s potential for plasticity. In the dentate gyrus (DG) subregion of the hippocampus, adult neurogenesis plays an important role both in memory and emotional processes such as depression. The neural pathway, DG-CA3 in this region shows remarkable learning-induced plasticity and is an important component of the brain’s stress-regulation circuitry. Though the mechanisms by which new neurons regulate stress and depression-related behaviour are largely unclear, they are likely to be critically dependent on their connections with downstream dorsal vs. ventral hippocampal subregions, which are involved in cognitive vs. emotional behaviours. Since the adult-born and pre-existing neuronal populations are each very large, understanding the role of the DG-CA3 pathway in stress-regulation and depression will require dissection of the circuits created during development vs. those created during adulthood.
This study will examine the influence of stress on the connectivity and plasticity of adult-born neurons in a rat model.
First, Dr. O’Leary will use a microscopal imaging technique to determine whether patterns of connectivity differ between pre-existing and adult-born neurons. Second, Dr. O’Leary will determine how stress in adult-hood modifies the pattern of connectivity in pre-existing and adult-born neurons. Following either acute or chronic restraint stress in adult-hood, anxiety-like behaviour, depressive-like behaviour, and patterns of neuronal connectivity will be measured.
Dr. O’Leary hypothesizes that stress will influence the pattern of connectivity of adult-born neurons within the ventral hippocampus, and these changes will correlate with anxiety- and depressive-like behaviours. This research will elucidate a novel mechanism by which stress contributes to depression in humans.
Lung function measures reflect the physiological state of the lungs, and are essential for the diagnosis and management of obstructive lung diseases such as asthma and chronic obstructive pulmonary disease (COPD), two common diseases with a huge burden on patients and health care systems. The measures are thought to have a genetic component, yet it is not known exactly how genes affect lung function. One mechanism by which genetic variation can influence lung function is through changing the amount of protein produced by that gene. This can be discovered by relating DNA sequence variations to mRNA or protein expression. Hence, to unravel the molecular mechanisms underlying lung function, it is very informative to study the genetic control of lung-specific gene expression.
Dr. Obeidat hypothesizes that a subset of lung function and obstructive lung diseases associated genetic loci act to change the level of expression of their gene product within the lung.
Dr. Obeidat is a member of a team that conducted genome-wide genotyping and gene expression analysis of lung tissue samples from ~1,200 individuals; the worlds largest study of its kind. The study identified ~17,000 loci where variants were related to the level of gene expression. Variants that are associated with both lung function and gene expression will be prioritized as being potentially causal for variation in lung function and will be investigated further. Further, bioinformatics methods will be used to identify molecular pathways and networks enriched in the genes driving lung function variation.
This approach represents the next frontier in complex diseases genetics and has been successfully implemented in other disease areas. With this integrative genomics method, Dr. Obeidat aims to use the new genetics derived knowledge to develop new therapies to alleviate common respiratory diseases.
HIV establishes a latent infection in CD4+ T cells that is not affected by current antiretroviral treatments. Because drug withdrawal allows viruses released from these cellular reservoirs to replicate, patients must remain on therapy for life to prevent re-emergence of the progressive disease. Although strategies to cure HIV infection are being discussed, development of an effective approach will require novel treatments that can eradicate reservoirs of latent virus. For this to occur, there is a need for a better understanding of HIV persistence, including knowledge of host and viral mechanisms required to establish and maintain latency. Formation of latent HIV reservoirs is thought to occur, in part, through infection of T cells that are either poorly activated or that revert to a non-activated state prior to death by viral cytopathic or host immune-mediated effects.
This study will investigate the role of the HIV pathogenic protein Nef in the establishment and maintenance of viral latency.
Dr. Mwimanzi hypothesizes that the Nef protein functions as a molecular “switch”, which regulates the activation threshold of virus-infected T cells. Using in vitro cell culture systems and panels of Nef variants that include site-directed mutants and patient-derived isolates, he will examine whether differences in Nef function affect the ability of a cell to establish or maintain latency.
It is anticipated that the results will help identify critical Nef motifs, evaluate interactions between Nef and host cell proteins, and elucidate viral and cellular mechanisms of HIV latency. With increased understanding of the mechanisms of HIV latency, this research has the potential to improve the health of those infected with HIV.
Inflammatory Bowel Diseases, including Crohn’s disease and ulcerative colitis are characterized by chronic intestinal inflammation and tissue damage. There are trillions of bacteria found within the human intestine and IBDs are thought to develop when mucus barriers that normally keep these bacteria inside the gastrointestinal tract become impaired, allowing bacteria to escape out of the gut lumen and causing chronic inflammation. While the role of epithelial cells in promoting barrier function is well known, the protective actions of the mucus barrier are relatively understudied.
Specialized secretory epithelial cells known as goblet cells within the gut lumen produce mucins known as Muc2 and pro-inflammatory proteins called RELM-ß. Through in vitro and in vivo studies, and microbiota analysis, Morampudi plans to define how these goblet cell proteins cooperatively protect the intestine from developing spontaneous colitis through the development of these products.Through tests with micelacking either Muc2 or RELM-ß, Dr. Morampudi has hypothesized that both proteins act together to protect the intestine from gut commensal bacteria. Muc2 provides a structural barrier, preventing bacteria from contacting the immune system, but when the mucus barrier is impaired, RELM-ß is induced to create an antimicrobial zone above the intestinal epithelium. Under conditions where expression of both proteins is impaired (such as by ER stress), the commensal bacteria are able to escape from the intestine and cause colitis/IBD.Ultimately, this research will provide insights as to how the development of spontaneous colitis can be prevented.
Because antiretroviral therapy has enabled people to live longer, those with HIV now face a growing epidemic of age-related chronic diseases such as chronic obstructive pulmonary disease (COPD). The reason for this increased risk, however, remains unknown. Compelling evidence suggests that HIV infection triggers an inflammatory process which causes the premature aging of inflammatory and structural cells due to cell exhaustion from repeated divisions and oxidative stress. This concept of “inflamm-aging” (coined by Claudio Franceschi) applies fittingly to the development of COPD as well, where the primary trigger is cigarette smoke.
Given the dual pro-inflammatory states of HIV and COPD, Dr. Leung hypothesizes that the accelerated development of emphysema in HIV is driven in part by inflammation-induced cell aging related to the HIV infection and potentiated in the lungs by cigarette smoke. Dr. Leung's laboratory has found peripheral leukocyte telomere lengths, a marker of cell senescence, are shorter in HIV-infected patients who also have COPD compared to HIV-infected patients without COPD. Those with the most severe airflow obstruction on spirometry and those with the greatest extent of emphysema as visualized on CT scanning also appear to have the shortest telomere lengths. The laboratory group is now exploring whether similar relationships hold in lung cells obtained from HIV-infected patients.
In Canada, stroke is the third leading cause of neurological disease and death. Although improved acute care has resulted in greater survival rates, an increased number of Canadians suffer long-term neurological disability and a decreased quality of life following a stroke. With an aging Canadian population, the need for efficient and effective diagnostic tools and rehabilitation strategies are critical so that stroke survivors can maintain independence and a high quality of life. Currently, the assessment of recovery and motor learning after a stroke focuses on neuroimaging techniques that indicate the status of gray matter within the central nervous system, which consists primarily of cell bodies. However, data characterizing how white matter supports motor learning and recovery after a stroke has been notably absent.
The goal of the study is to explore and understand the mechanisms associated with learning-dependent changes of white matter in the central nervous system. The proposed research plan will attempt to, firstly, understand whether motor learning is associated with changes in the white matter micro-structure and, secondly, relate changes in brain structure and neurophysiology to learning and functional recovery after stroke.
The intended research will provide unprecedented insight into areas of the stroke-injured brain that respond to motor learning. More importantly, this work will enhance the understanding of the effects of motor learning on functional recovery and generate the opportunity to develop novel therapeutic interventions for the growing population of individuals living with the after-effects of stroke.
