BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10618195
• 负责人: Raghu VEMUGANTI
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618195
• 关键词: Acute; Age; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptotic; Award; Brain; Brain Injuries; Brain Ischemia; Central Nervous System; Cerebral Ischemia; Cerebrovascular Circulation; Clinical Trials; Cognitive; Combined Modality Therapy; Cortical Contusions; DNA; Data; Diabetes Mellitus; Epigenetic Process; Event; Family; Functional disorder; Funding; Genes; Goals; Grant Review; Health; Hour; Human Resources; Industry; Inflammation; Injury; Ischemic Brain Injury; Ischemic Stroke; Journals; Long-Term Effects; Mediating; Metabolism; MicroRNAs; Middle Cerebral Artery Occlusion; Modification; Molecular; Motor; Mus; Neurobiology; Neurologic Deficit; Neurologic Dysfunctions; Neurons; Neurosciences; Outcome; Oxidative Stress; Paper; Parkinson Disease; Pathologic; Pathology; Pharmaceutical Preparations; Phosphorylation; Play; Prevention; Protein Family; Proteins; Publications; Publishing; Quality of life; Recovery of Function; Research; Resveratrol; Rodent; Role; Science; Scientist; Seminal; Services; Signal Transduction; Small RNA; Societies; Source; Stroke; Stroke prevention; Testing; Toxic effect; Transcriptional Regulation; Translations; Traumatic Brain Injury; Traumatic Brain Injury recovery; Treatment Efficacy; Ubiquitination; Untranslated RNA; Veterans; alpha synuclein; career; circular RNA; cognitive function; comorbidity; controlled cortical impact; derepression; disability; dysbiosis; efficacious treatment; endoplasmic reticulum stress; epitranscriptomics; functional gain; functional outcomes; gut dysbiosis; gut inflammation; gut microbiome; improved; indexing; mouse model; neurochemistry; neurological recovery; neuron loss; neuroprotection; neuropsychiatry; neurotoxicity; new therapeutic target; novel therapeutics; polyphenol; post stroke; prevent; programs; promoter; prophylactic; sex; stroke model; stroke therapy; transcription factor

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.

Vemuganti 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功能恢复处于领先地位。 造成现役军人和退伍军人残疾的原因，并且他们在战争结束后的几十年里都遭受着这些影响 初始事件。 数小时内开始并持续数天的氧化应激和内质网 (ER) 应激可促进 神经元死亡导致 TBI 后长期神经功能障碍因此，目前资助的优点审查。 Vemuganti 博士的格兰特将检验抗氧化剂联合疗法（以防止形成 ROS 并诱导 ROS 的处理）保护大脑并促进两者的长期功能增益 我们进一步检验了预防氧化应激和内质网应激的假设。 一起使用更能有效地保护大脑并促进 TBI 后的神经功能恢复。我们还将进行测试。 控制氧化应激可降低帕金森病 (PD) 病理倾向的假设 TBI 后，这些研究将使用一种成熟的 TBI 小鼠模型，称为受控皮质冲击损伤。 将研究运动功能、认知功能和神经精神功能以及皮质挫伤 总体而言，本项目将帮助我们找到一种治疗方法。 通过减少氧化来最大程度地减少 TBI 后继发性脑损伤和神经功能障碍的药物组合 TBI 后的压力和 ER 压力 长期目标是提供一种治疗方法来帮助军人和退伍军人。 患有 TBI 的人。 中风会导致显着的运动、认知和神经精神功能障碍，但尚无有效的治疗方法。 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，调节。 特定的 microRNA (miRNA) 可以在啮齿动物中提供神经保护和中风后更好的功能恢复。 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。 通过使用 miR-21 模拟物治疗而增加，且无任何毒性，因此，在目前的一项优点审查补助金中。 等待中，Vemuganti 博士将测试以下假设：miR-21 模拟物是一种有效的神经保护疗法，可预防 使用称为短暂性大脑中动脉闭塞（MCAO）的小鼠中风模型来研究中风后脑损伤。 中风治疗学术产业圆桌会议 (STAIR) 规定了许多测试新疗法的标准。 接下来，我们将测试治疗效果、长期运动、认知和神经精神方面的窗口 结果、性别、年龄和糖尿病（中风共病）对 miR-21 模拟物诱导的影响 短暂 MCAO 后的神经保护最近的研究表明肠道微生物组影响炎症。 因此，我们将进一步检验 miR-21 介导中风后的假设。 神经保护是由于预防肠道微生物群失调而导致炎症减少。 目标是将 miR-21 确立为一种神经保护性 miRNA，具有减少中风后脑损伤的潜力， 如果成功，这些研究将通过纠正肠道菌群失调和炎症来改善功能恢复。 建立 miR-21 作为一种新疗法来帮助中风的服役人员和退伍军人。

项目成果

MMP-12 knockdown prevents secondary brain damage after ischemic stroke in mice.

MMP-12 敲低可预防小鼠缺血性中风后的继发性脑损伤。

• 发表时间: 2022-12
• 影响因子: 4.2
• 作者: Arruri, Vijay;Chokkalla, Anil K;Jeong, Soomin;Chelluboina, Bharath;Mehta, Suresh L;Veeravalli, Krishna Kumar;Vemuganti, Raghu
• 通讯作者: Vemuganti, Raghu