BLRD Research Career Scientist Award Application

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The PI, Mark S. Kindy, Ph.D., has been studying the mechanisms and pathways associated with a number of neurological and neurodegenerative disorders. These include, Alzheimer’s disease (AD), stroke, Parkinson’s disease (PD), traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), spinal cord injury (SCI), among others. All of these disorders are afflictions that are present in the VA population and contribute significantly to the overall health of the Veterans. The overarching goal is to understand the mechanisms involved in the disease processes and to develop therapeutic approaches to treat them. I have three basic areas of research that we focus on. The first program is centered around stroke and the impact of negative vascular health factors (such as: obesity, diabetes, age, salt sensitivity hyperlipidemia, and hypertensivity) on the induction of reactive oxygen species (ROS) production and activation of the inflammation (inflammasome). We have shown that aged animals with the risk factors have worse outcomes and recovery is exacerbated due to the presence of both systemic and neuroinflammation. The generation of better clinical models of stroke to test these risk factors and health disparities following injury. Studies using low-density lipoprotein receptor (ldlr) deficient mice with and without high fat diet are being used to study the impact of oxidized phospholipids (OxPLs) on stroke outcomes. Mice expressing OxPL antibodies will be tested for protection from stroke. Finally, we are examining the impact of chronic kidney disease, left ventricular hypertrophy and FGF23 on stroke and stroke outcomes. Mice with targeted deletion of the fgfr4 gene or overexpression of the FGF23 are being examined for stroke outcomes. These studies will better capture the true nature of veterans and civilians who have a stroke and provide a better approach to treating the disease. A second line of research focuses on the role of serum amyloid A (SAA) proteins in the pathogenesis of stroke. Recent studies have implicated SAAs in innate immunity and various disorders, however the precise mechanism eludes us. SAAs are elevated following stroke (cerebral ischemia) and TBI, and our studies show that SAA increases the cytokine interleukin-1 (IL-1), which is mediated by Nod-like receptor protein 3 (NLRP3) inflammasome, cathepsin B and caspase-1 and may play a role in the pathogenesis of neurological disorders. Using transgenic and gene deleted mice as well as AAV expressing constructs we are evaluating the impact of SAA on stroke and other neurological diseases. Another line of research focuses on serum amyloid P component (SAP), which is found in all amyloids and studies have suggested that it plays an integral role in the formation, progression, and maintenance of the amyloid disease processes. The amyloid diseases include: AD, PD (tau, -synuclein, TDP-43), tauopathies, CTE, ALS (SOD1, TDP-43, C9ORF72), systemic amyloids (AA, TTR, amylin), Huntington’s disease (HD), ABri and ADan. Inflammation modifies SAP function, and inflammatory signaling pathways impair cognitive function in vivo. Our long-term goal is to determine the mechanisms regulating SAP function, particularly within the setting of AD and inflammatory diseases. Consequently, the objective of this grant is to characterize the role for SAP in inflammation and AD. We have developed and amassed various transgenic and gene deleted mice as well as viruses and inhibitors to determine the impact of SAP in the amyloid diseases. Since both SAA and SAP are produced mainly in the liver, we are working with Ionis Pharmaceuticals in the design and testing of antisense oligonucleotides (ASOs) as therapeutic approaches to these disorders. In addition, we are working with clinicians at the Haley VA and other VAs (Boston CTE Center) and Universities around the US to correlate the animal studies with human disease. Using autopsy tissues, blood, CSF and other reagents to validate the studies in our mouse and rat models. This is critical to our basic understanding of the disease process and in the development of therapeutics for treatment.