BLRD Research Career Scientist Award Application

Vemuganti博士目前的研究是寻找预防继发性脑损伤的治疗方法， 创伤性脑损伤（TBI）或缺血性中风后的神经恢复。创伤性脑损伤和中风 军人和退伍军人残疾的原因，以及他们在战争结束后几十年内遭受的影响 初始事件。 氧化应激和内质网（ER）应激在数小时内开始并持续数天， 神经元死亡，导致TBI后长期神经功能缺损。因此，目前供资的绩效审查 Vemuganti博士的格兰特将测试一种抗氧化剂联合治疗（以防止形成 ROS和诱导ROS的处置）保护大脑，并促进两者的长期功能增益。 不同年龄组的性别。我们进一步验证了防止氧化应激和内质网应激 联合应用更有效地保护脑组织，促进脑外伤后神经功能的恢复。我们还将测试 控制氧化应激降低帕金森病（PD）病理倾向的假设 在TBI之后这些研究将使用一种成熟的TBI小鼠模型，称为受控皮质撞击损伤。 运动功能，认知功能和神经精神功能将被研究，以及皮质挫伤， 进行TBI并用联合疗法治疗的小鼠。总的来说，本项目将帮助我们找到一个 一种通过减少氧化损伤来最大限度地减少TBI后继发性脑损伤和神经功能障碍的药物组合 应激和ER应激。长期目标是提供一种治疗方法来帮助服务人员和退伍军人 谁遭受创伤性脑损伤。 中风促进显著的运动、认知和神经精神功能障碍。然而，没有有效的 预防中风后脑损伤和神经功能缺损的治疗。最近的研究表明， 特异性microRNAs（miRNAs）导致啮齿动物中风后的神经保护和更好的功能恢复。 miRNA miR-21具有抗凋亡和抗炎作用。我们观察到大脑中的miR-21水平 通过用miR-21模拟物处理而没有任何毒性增加。因此，在目前正在进行的绩效审查补助金中， Vemuganti博士将测试miR-21模拟物是一种有效的神经保护疗法的假设， 使用称为短暂性大脑中动脉闭塞（MCAO）的小鼠中风模型来观察中风后脑损伤。 中风治疗学术行业圆桌会议（STAIR）规定了许多测试新疗法的标准。 在此之后，我们将测试治疗效果，长期运动，认知和神经精神的窗口 结果，性别、年龄和糖尿病（卒中共病）对miR-21模拟诱导的 短暂性MCAO后的神经保护作用。最近的研究表明，肠道微生物组会影响炎症 在中风后的大脑中因此，我们将进一步验证miR-21介导的卒中后 神经保护是由于预防肠道微生物组生态失调导致炎症减少。整体 我们的目标是将miR-21作为一种神经保护性miRNA，有可能减少卒中后脑损伤， 通过纠正肠道生态失调和炎症改善功能恢复。如果成功，这些研究将导致 建立miR-21作为一种新的治疗方法，以帮助患有中风的服务人员和退伍军人。

Dr. Vemuganti’s current research is to find therapies for preventing secondary brain damage and to promote neurological recovery following either traumatic brain injury (TBI) or ischemic stroke. TBI and stroke are leading causes of disability in service personnel and Veterans and they suffer the effects of these for decades after the initial events. Oxidative stress and endoplasmic reticulum (ER) stress that starts within hours and continues for days promotes neuronal death that lead to long-term neurological deficits after TBI. Hence, the currently funded Merit Review Grant of Dr. Vemuganti will test the hypothesis that an antioxidant combination therapy (to prevent the formation of ROS and induce the disposal of ROS) protects the brain and promotes long-term functional gains in both sexes at different ages after TBI. We further test the hypothesis that preventing oxidative stress and ER stress together is more efficacious to protect the brain and to promote neurological recovery after TBI. We will also test the hypothesis that controlling oxidative stress decreases the propensity of Parkinson’s disease (PD) pathology after TBI. The studies will use a well-developed mouse model of TBI known as controlled cortical impact injury. Motor function, cognitive function and neuropsychiatric function will be studied as well as cortical contusion in mice subjected to TBI and treated with the combo therapies. Overall, the present project will help us to find a drug combo that minimizes secondary brain damage and neurologic dysfunction after TBI by curtailing oxidative stress and ER stress after TBI. The long-term goal is to provide a therapy to help service personnel and Veterans who suffer a TBI. Stroke promotes significant motor, cognitive and neuropsychiatric dysfunction. However, there is no efficacious therapy to prevent post-stroke brain damage and neurologic deficits. Recent studies showed that modulating specific microRNAs (miRNAs) leads to neuroprotection and better functional recovery after stroke in rodents. The miRNA miR-21 is anti-apoptotic and anti-inflammatory. We observed that miR-21 levels in the brain increases by treatment with a miR-21 mimic without any toxicity. Hence, in a Merit Review Grant that is currently pending, Dr. Vemuganti will test the hypothesis that miR-21 mimic is a potent neuroprotective therapy to prevent post-stroke brain damage using a mouse stroke model called transient middle cerebral artery occlusion (MCAO). Stroke Treatment Academic Industry Roundtable (STAIR) stipulated many criteria for testing new therapies. Following those, we will test the window of therapeutic efficacy, long-term motor, cognitive and neuropsychiatric outcomes, effect of sex, age and diabetes (comorbid condition for stroke) on miR-21 mimic-induced neuroprotection following transient MCAO. Recent studies showed that gut microbiome influences inflammation in the post-stroke brain. Hence, we will further test the hypothesis that miR-21 mediated post-stroke neuroprotection is due to prevention of gut microbiome dysbiosis leading to curtailed inflammation. The overall goal is to establish miR-21 as a neuroprotective miRNA with potential to decrease post-stroke brain damage and improve functional recovery by rectifying gut dysbiosis and inflammation. If successful, these studies leads to establishment of miR-21 as a new therapy to help service personnel and Veterans who suffer a stroke.