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Cerebrovascular Session
Establishing A Clinically Relevant Animal Model of ...
Establishing A Clinically Relevant Animal Model of Intracerebral Hemorrhage_ Investigating The Effect Of Hypertension
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Video Transcription
My name is Anthony Anzalone. I'm a third-year medical student at Wake Forest School of Medicine. I'm grateful for this opportunity to present our work as part of the DEVIL-ANS Virtual Cerebrovascular Session. Today, I'll be discussing research that I've been working on under the guidance of my mentor, Dr. Stacy Wolf. The title of my presentation is Establishing a Clinically Relevant Animal Model of Intracerebral Hemorrhage, Investigating the Effect of Hypertension, Metabolic Syndrome, and Sex on the Histologic and Sensory Motor Response in the REN2 Transgenic Rat. To begin, I would like to declare that I have no financial disclosures or conflicts of interest. ICH is a catastrophic condition. Despite the devastating consequences, little progress has been made toward the development of an effective treatment that improves functional outcomes. There are likely many reasons for this, but a few relevant to this presentation include the fact that mechanisms of ICH are heterogeneous in nature, and preclinical models of ICH have largely failed to mirror the comorbidities of the affected patient population. Primary injury is due to mechanical insult that occurs from dissection and mass effect of the hematoma. Secondary injury is the immediate consequence of the primary insult and is due to blood products within the perigema. Secondary injury leads to an excitotoxic environment that causes oxidative damage and very quickly the mobilization of pro-inflammatory pathways that propagate the neurological damage of ICH. Research has demonstrated that secondary injury cascades play a significant role in the neurological consequences of ICH. We postulate that by better understanding of the secondary injury pathways, viable therapeutic targets may be explored. Upon examining the literature, it's been noted that many of the preclinical studies examining ICH have been conducted in healthy, young male rodents. This is problematic because features such as the metabolic syndrome, advanced age, both of which are important predisposing factors to ICH, prime the immune system toward a pro-inflammatory state which may influence secondary brain injury. The bottom line is that most preclinical models used in ICH research have not optimally reflected the comorbidities of those who suffer from ICH, and this may account for failed translation of preclinical findings. This leads us to the objectives of the current study. We propose that by utilizing the RIN2 transgenic rat, we can develop a more clinically relevant and translatable preclinical model of ICH. The aims of this study are to validate that the RIN2 transgenic rat does indeed recapitulate the baseline pathological conditions of the affected ICH population. The RIN2 transgenic rat overexpresses the murine RIN2 gene. This causes the development of chronic hypertension as well as features of metabolic syndrome, including obesity, insulin resistance, and hypertensive end-organ damage. In this study, we are utilizing both male and female transgenic RIN2 rats as well as control sprague dolly rats. The study is being completed in two phases. In the first, which has already been completed, we sought to confirm that the transgenic animals were indeed chronically hypertensive. We also sought to determine whether we could reliably conduct sensory motor testing. The second phase of this study, which has not yet been completed, will include histologic and immunohistochemical examinations of the brains of the animals with an emphasis on examining both between strain, between sex differences at various ages. The reason for this is because the transgenic animals are known to demonstrate end-organ damage that is analogous to that which is seen in humans with chronic hypertension. Moreover, there is evidence of delayed disease severity in the female sex. As expected, we verified that the transgenic animals did have a higher blood pressure compared to the control animals. And in both groups, male animals had higher blood pressure compared to female animals. For sensory motor testing, there were no significant between strain differences at weeks 20, 22, 23, or 24. However, a significant difference was identified at week 21, which was found to be isolated to the evoked for limb response test. So far, we are on track to demonstrate that the REN2 transgenic rat better mimics the pathological conditions of those affected by ICH, as these rats demonstrate hypertension, insulin resistance, and obesity. In addition, the ability to administer serial sensory motor testing and obtain stable results that are similar to that of our control animals indicates that we should be able to reliably detect experimentally-induced deficits. Going forward, we do intend to complete the second phase of this endeavor and assess histologic and immunohistochemical profiles of the brains of both transgenic and control animals. Moving beyond this study, we intend to utilize the REN2 transgenic rat to characterize the neuroinflammatory profile in the context of experimentally-induced ICH. By doing this, we hope to be able to one day identify unique therapeutic targets to combat secondary brain injury associated with ICH. Thank you.
Video Summary
In this video, Anthony Anzalone, a third-year medical student at Wake Forest School of Medicine, presents his research on establishing a clinically relevant animal model of intracerebral hemorrhage (ICH) and investigating the effect of hypertension, metabolic syndrome, and sex on the histologic and sensory motor response. He highlights the lack of progress in developing effective treatments for ICH and the limitations of current preclinical models. By utilizing the REN2 transgenic rat, which develops chronic hypertension and features of metabolic syndrome, Anzalone aims to create a more accurate model that mirrors the comorbidities of ICH patients. He discusses the preliminary findings regarding blood pressure and sensory motor testing, and plans to further analyze histologic and immunohistochemical profiles to identify potential therapeutic targets for ICH. Anzalone gives credit to his mentor, Dr. Stacy Wolf, and acknowledges the DEVIL-ANS Virtual Cerebrovascular Session for the opportunity to present his work.
Keywords
intracerebral hemorrhage
hypertension
metabolic syndrome
animal model
sensory motor response
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