BLRD Research Career Scientist Award Application

维穆甘蒂博士目前的研究是寻找预防继发性脑损伤的疗法，并促进 创伤性脑损伤(TBI)或缺血性中风后的神经恢复。TBI和中风领先 造成服役人员和退伍军人残疾的原因，他们在此后的几十年里一直遭受这些原因的影响 最初的事件。 在几小时内开始并持续数天的氧化应激和内质网应激促进 导致脑外伤后长期神经功能障碍的神经元死亡。因此，目前得到资助的功绩审查 Vemuganti博士的Grant将测试抗氧化剂联合疗法(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收益 颅脑损伤后不同年龄的性别。我们进一步检验了预防氧化应激和内质网应激的假设 联合用药能更有效地保护脑，促进脑损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)病理倾向的假说 在TBI之后。这项研究将使用一种发展良好的脑外伤小鼠模型，称为受控皮质撞击损伤。 将研究运动功能、认知功能和神经精神功能以及皮质挫伤。 小鼠接受创伤性脑损伤，并用联合疗法治疗。总体而言，本项目将帮助我们找到一个 通过抑制氧化将脑外伤后继发性脑损伤和神经功能障碍降至最低的药物组合 脑创伤后应激和内质网应激。长期目标是提供一种治疗方法，帮助服役人员和退伍军人 他们遭受了脑外伤。 中风会导致严重的运动、认知和神经精神障碍。然而，没有灵丹妙药。 预防中风后脑损伤和神经功能障碍的治疗。最近的研究表明，调制 特定的microRNAs(MiRNAs)对啮齿动物卒中后的神经保护和更好的功能恢复起到了作用。 MiRNA miR-21具有抗细胞凋亡和抗炎作用。我们观察到大脑中miR-21的水平 用miR-21模拟物处理后增加，没有任何毒性。因此，在功绩审查拨款中，目前 在悬而未决的情况下，维穆甘蒂博士将检验miR-21模拟是一种有效的神经保护疗法以预防 使用一种名为短暂性大脑中动脉闭塞(MCAO)的小鼠中风模型研究中风后的脑损伤。 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。 随后，我们将测试治疗效果的窗口、长期运动、认知和神经精神状态 预后、性别、年龄和糖尿病(卒中的共病)对miR-21模拟诱导的影响 短暂性大脑中动脉阻塞后的神经保护。最近的研究表明，肠道微生物群影响炎症 在中风后的大脑中。因此，我们将进一步检验miR-21介导的卒中后的假设 神经保护是由于防止肠道微生物群失调导致炎症减少。整体而言 目标是建立miR-21作为神经保护性miRNA，具有减少中风后脑损伤和 通过纠正肠道生物失调和炎症，促进功能恢复。如果成功，这些研究将导致 建立miR-21作为一种新的疗法，以帮助遭受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.