To address questions regarding how ion channels modulate neuronal function and ultimately behavioral output, my lab makes and uses transgenic mice that have been genetically engineered to either lack specific genes, over express specific gene products or produce gene products that have been functionally mutated. Using a multidisciplinary approach that combines aspects of modern molecular biology, behavioral neuroscience and electrophysiology, the lab is currently pursuing a number of broad-based research domains:
Within the millisecond/second time domain, L-VGCCs regulate neuronal excitability in an activity dependent manner by gating the calcium influx that is required for the activation of calcium activated potassium channels. At the other end of the time spectrum, L-VGCCs gate calcium influx that activates transcription factors that regulate gene expression which often has long-term or near permanent consequences. Although a great deal has been learned in the last two decades regarding the role that L-VGCCs play in regulating neuronal function, our knowledge of the fine details is still somewhat lacking. Specifically, for the majority of neuronal functions to which L-VGCCs have been ascribed, it is not know which is the relevant subtype (CaV1.2 or CaV1.3) or if they are both involved, what is the relative contribution of the two different subtypes. This is in large part due to the fact that at present there are no pharmacological agents that are subtype specific. In light of recent data suggesting that CaV1.2 and CaV1.3 are biophysically different and previous work demonstrating significant differences in distribution, it has become increasingly apparent that a better understanding of calcium mediated changed in neuronal function will require us to be able to distinguish the relative contributions of two different subtypes. Therefore my laboratory has been using a multidisciplinary approach to address two broad research domains: age related changes in L-VGCC function and the role that L-VGCCs play in the consolidation and extinction of Pavlovian conditioned fear.
Mounting clinical and experimental data suggest that cardiovascular disease (CVD) risk factors that promote vascular remodeling and dysfunction are associated with cognitive impairment, and are significant risk factors for the development of AD dementia. These studies include observations directly linking pathways associated with vascular injury such as hemostasis, angiogenesis, and hypertension to AD, leading to the hypothesis that CVD risk factors may act via common mechanisms to promote AD development or progression. For example, current data show that plaques, tangles, and CVD risk factors all upregulate expression of plasminogen activator inhibitor 1 (PAI-1), an independent CVD risk factor. Recent studies also suggest that PAI-1 may be a diagnostic biomarker and/or a risk factor for clinical AD, and PAI-1 expression increases with age, the most significant risk factor for AD dementia. PAI-1 is best understood for its role regulating fibrinolysis and wound, and in mouse models of AD PAI-1 deficiency is correlated with improved outcomes. In preliminary data presented here in the 5XFAD amyloidogenic mouse model we find that significant vascular remodeling occurs concurrently with amyloid plaque development and cognitive impairment. These changes are associated with reductions in cortical blood flow and increased PAI-1 expression. RNA-Seq and pathway analysis identify highly significant increases in gene expression in pathways known to be involved in vascular remodeling in the 5XFAD mice compared to Wt littermates, including pathways associated with angiogenesis and cardiovascular development. We also find that pharmacologic inhibition of PAI-1 in 5XFAD mice reduces abnormal vascular remodeling and improves cognition in the 5XFAD mice, without reducing plaque burden; and importantly that expression of genes within the vascular remodeling pathways are dramatically reduced in 5XFAD mice receiving the PAI-1 inhibitor. Based on the current literature and our preliminary data we will test the novel hypothesis that there is a causal relationship between vascular remodeling, and impaired cognition in the context AD, and that PAI-1 plays a critical role promoting pathologic vascular remodeling during AD development and progression.
In addition, we have a number of active collaborations at the University of Michigan as well as at other institutions which include a number of translational projects that emphasize specific disease models:
Neurobiological substrates of psychiatric disease states
Neurobiological basis of Epilepsy
Cognitive aging and age-related neuroinflammation
Historically, the focus of aging research has been centered on treating specific age-associated diseases as they arise. This approach, however, has led to a division of attention and resources around each individual disease. The recent introduction of the “geroscience hypothesis” has called for a more unified strategy to focus instead on the most common risk factor associated with many ailments: aging. Under this hypothesis, therapeutic approaches that address the aging process itself could act to stave off or delay the onset of disease, potentially reduce disease severity, or even halt disease progression. As new therapeutics are discovered and tested for their potential benefits in lifespan extension, our lab is interested in evaluating those same therapeutics for their efficacy in combating cognitive aging, or the natural process by which older adults experience a decline in cognitive function, such as memory. Identifying a therapeutic that is effective at extending lifespan and delaying cognitive aging will preserve both bodily and cognitive healthspan and improve overall quality of life as we grow older.
Neuronal development and dysregulated gene expression in Down Syndrome
Down Syndrome (DS) is the most common genetic cause of intellectual disability in the world, occurring approximately 1 in every 700 births. It results from trisomy of human chromosome 21 (HSA21) and is characterized by physical and psychomotor impairments, and neurodevelopmental delays. These complex phenotypes are likely a culmination of multiple gene interactions, further complicating efforts to investigate, isolate, and potentially develop therapeutics against the primary contributors. In collaboration with the Bing Ye Lab here at the University of Michigan, we are investigating several HSA21 genes for their role in neurodevelopment and the determination of cognitive impairment in mouse models of DS. Through the use of murine genetics, behavioral studies, and both functional and morphological neuroscience techniques, we hope to improve the understanding of this disorder and ultimately help those individuals and their families to live happy and healthy lives.