The Role of Gut Microbiota in Neointimal Hyperplasia After Vascular Injury

 简介(申请人提供)：何凯伦的职业目标是成为一名独立资助的学术血管外科医生兼科学家，推动血管外科领域的发展，并特别减轻血管成形术/支架和搭桥手术等干预措施后再狭窄的负担。她在耶鲁大学攻读分子生物物理学和生物化学本科课程，在哈佛大学接受医学培训，在布里格姆妇女医院接受外科和血管培训，并在布里格姆妇女医院和贝丝以色列女执事医院接受博士后研究培训，为实现这些目标奠定了坚实的基础。现在在西北大学，她的角色是开发血管外科的基础科学研究项目，她得到了系里和导师的无条件支持。她也有动力和智慧来开发微生物组的研究方向，这对她来说是新的，但也是令人兴奋的、创新的和新颖的。何博士的近期目标是利用K08奖项的受保护研究时间和导师架构，加强她在肠道微生物群方面的知识和科研技能，有效研究肠道微生物和微生物衍生代谢物调节新生内膜增生的机制，最终目标是开发补充或替代的饮食策略，调节微生物群，以降低动脉介入治疗后再狭窄的风险。在可预见的未来，由于肥胖、高血压和糖尿病的日益流行，动脉粥样硬化仍将是一个主要的公共卫生问题。此外，作为动脉粥样硬化干预失败的原因之一的再狭窄，尽管经过几十年的研究，仍然是一个棘手的问题，这突显了新方法的重要性。尽管我们与肠道微生物区系存在共生关系，但改变肠道微生物数量或组成的扰动已被认为与慢性炎症性疾病有关，包括肥胖、糖尿病、动脉粥样硬化和炎症性肠病。在某些情况下，这种关系可能涉及肠道微生物衍生的代谢物，如短链脂肪酸(SCFA)，它们是由微生物发酵膳食纤维产生的。何博士过去一年半的初步工作表明，近亲交配的大鼠在接受抗生素治疗后，颈动脉血管成形术后的新生内膜增生加剧，而同时补充丁酸钠的效果被逆转，丁酸钠是一种主要的SCFA。此外，丁酸盐对体外培养的血管平滑肌细胞具有抗增殖和抗迁移作用。因此，我们假设肠道微生物区系通过产生SCFA来影响动脉损伤反应。为了研究这一假说，本研究的目的是(1)评估肠道微生物组在小鼠新生内膜增生模型中的功能作用；(2)确定微生物组来源的SCFA是否通过调节全身和/或局部炎症来调节新生内膜增生；(3)确定微生物组来源的SCFA是否通过直接调控细胞增殖、迁移和/或细胞凋亡来调控新生内膜增生。西北大学和芝加哥大学的科学环境、导师团队和多学科咨询委员会，以及拟议的职业发展计划，都围绕着何博士的目标，即利用受保护的时间来丰富她在表征和操纵微生物群并将其应用于新生内膜增生发病机制方面的工作知识。西北大学的范伯格心血管研究所是何博士提出这项建议的主要地点。梅琳娜·基布医生是何医生的主要导师，也是西北大学外科系一位经验丰富的内科科学家。Kibbe博士的实验室在新生内膜增生和动脉粥样硬化的动物模型以及血管生物学方面拥有专业知识。何博士在范伯格心血管研究所的实验室距离Kibbe博士的实验室很近，她可以使用西北大学的多个核心设施、一个动物设施和科学研究顾问。芝加哥大学生物科学分部的胃肠病学分部是这项提议的第二个地点。何博士的共同导师尤金·B·张博士是芝加哥大学肠道微生物群和宿主-微生物相互作用方面的一名经验丰富的研究员。他的研究专攻肠道上皮、生物学/病理生物学、依赖培养和非培养的方法来研究肠道微生物区系，以及粘膜免疫学。他的实验室位于最先进的Nnapp生物医学发现中心，包括NIDDK P30消化系统疾病研究核心中心，距离西北大学芝加哥校区只有20分钟的车程。在颁奖期间，何博士将在两个地点选出正式的课程作业。这项建议和集合的环境和指导支持计划解决了双重目的：通过结构化的指导和受保护的科学框架提高何博士的科学技能，并确定肠道微生物群在新生内膜增生中的机械作用。西北大学和芝加哥大学坚定不移地支持何博士实现这些目标，将为她提供必要的技能，以实现她成为一名独立外科科学家的目标。

 DESCRIPTION (provided by applicant): Karen J. Ho's career goals are to become an independently-funded, academic vascular surgeon- scientist, advance the field of vascular surgery, and specifically reduce the burden of restenosis after interventions such as angioplasty/stenting and bypass surgery. She has a sound foundation for achieving these objectives through her undergraduate studies in molecular biophysics and biochemistry at Yale, medical training at Harvard, surgical and vascular training at Brigham and Women's Hospital, and postdoctoral research training at Brigham and Women's Hospital and Beth Israel Deaconess Hospital. Now at Northwestern University, her role is to develop a basic science research program in vascular surgery, and she has unconditional support from her Department and mentors. She also has the drive and intellect to develop a research direction in the microbiome that is new to her but which is exciting, innovative, and novel. Dr. Ho's immediate goal is to use the protected research time and mentorship structure of the K08 Award to enhance her knowledge and scientific research skills in the gut microbiome to effectively study the mechanism by which gut microbes and microbe-derived metabolites regulate neointimal hyperplasia, with the eventual goal of developing complementary or alternative dietary strategies that modulate the microbiome to reduce the risk of restenosis after arterial interventions. Atherosclerosis will continue to be a major public health problem in the foreseeable future due to the increasing prevalence of obesity, hypertension, and diabetes. Furthermore, restenosis as a cause of failure of interventions for atherosclerosis continues to be an intractable problem despite decades of research, underscoring the importance of a novel approach. Although we have a symbiotic relationship with our gut microbiota, perturbations that alter the quantity or makeup of gut microbes have been linked to chronic inflammatory diseases including obesity, diabetes, atherosclerosis, and inflammatory bowel disease. In certain cases, this relationship may involve gut microbe- derived metabolites such as short chain fatty acids (SCFA), which are produced by microbial fermentation of dietary fiber. Dr. Ho's preliminary work over the past year and a half shows that inbred rats treated with antibiotics have exacerbated neointimal hyperplasia after carotid angioplasty, an effect that is reversed by concomitant supplementation with sodium butyrate, a major SCFA. Furthermore, butyrate has an anti- proliferative and anti-migratory effect in vascular smooth muscle cells in vitro. Thus, we hypothesize that gut microbiota influence the arterial injury response through the production of SCFA. To investigate this hypothesis, the aims of this proposal are (1) to evaluate the functional role of the gut microbiome in a murine model of neointimal hyperplasia, (2) to determine if microbiome-derived SCFA regulate neointimal hyperplasia through modulation of systemic and/or local inflammation, and (3) to determine if microbiome-derived SCFA regulate neointimal hyperplasia through direct modulation of cellular proliferation, migration, and/or apoptosis. The scientific environment at Northwestern University and the University of Chicago, the mentorship team and multidisciplinary Advisory Committee, and the proposed Career Development Plan are centered around Dr. Ho's objective to use protected time to enrich her working knowledge of characterizing and manipulating the microbiome and applying these to the pathogenesis of neointimal hyperplasia. Northwestern University's Feinberg Cardiovascular Research Institute is Dr. Ho's principal location for this proposal. Dr. Melina Kibbe is Dr. Ho's primary mentor and an experienced physician-scientist in the Department of Surgery at Northwestern University. Dr. Kibbe's laboratory has expertise in animal models of neointimal hyperplasia and atherosclerosis and in vascular biology. Dr. Ho's lab in Feinberg Cardiovascular Research Institute is located in close proximity to Dr. Kibbe's and she has access to multiple Northwestern University core facilities, an animal facility, and advisors in scientific research. The University of Chicago's Biological Sciences Division Section of Gastroenterology is a second site for this proposal. Dr. Eugene B. Chang, Dr. Ho's co-mentor, is a seasoned investigator at the University of Chicago in the gut microbiome and host-microbial interactions. His research specializes in intestinal epithelial, biology/pathobiology, cultivation-dependent and cultivation-independent approaches to studying gut microbiota, and mucosal immunology. His lab in the state-of-the-art Knapp Center for Biomedical Discovery includes the NIDDK P30 Digestive Diseases Research Core Center and is only 20 minutes away by car from the Northwestern University Chicago campus. During the award period, Dr. Ho will elect formal coursework at both sites. This proposal and the assembled environmental and mentoring support plan address dual purposes: to advance Dr. Ho's scientific skills through a structured mentorship and protected scientific framework and to determine the mechanistic role of the gut microbiome in neointimal hyperplasia. The unwavering support of both Northwestern University and University of Chicago to Dr. Ho to meet these objectives will provide her with the skills necessary to achieve her goal of becoming an independent surgeon scientist.