The role of adipocyte gamma-secretase in regulation of inflammatory signaling

脂肪细胞γ-分泌酶在炎症信号调节中的作用

• 批准号: 9757774
• 负责人: David Sparling
• 金额: $ 12.47万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-07 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757774
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Affect; Alzheimer' s Disease; Award; Basic Science; Biology; Biometry; CCL2 gene; Cell physiology; Cell surface; Cells; Childhood; Childhood diabetes; Clinical; Complex; Data; Data Analyses; Development; Diabetes Mellitus; Disease Progression; Doctor of Philosophy; Endocrine; Endocrinology; Environment; Epidemiology; Event; Extramural Activities; Fellowship; Foundations; Functional disorder; Funding; Future; GLUT 4 protein; GLUT4 gene; Gap Junctions; Gene Expression; Genetic Transcription; Goals; Health Sciences; Hypersensitivity; IL6 gene; Immune; Immune signaling; Immune system; Immunology; In Vitro; Inflammation; Inflammatory; Instruction; Insulin; Insulin Resistance; Integral Membrane Protein; Macrophage Activation; Malignant Neoplasms; Mediating; Medicine; Mentors; Metabolic; MicroRNAs; Multienzyme Complexes; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oklahoma; PTEN gene; Pathway interactions; Patients; Pediatrics; Phenotype; Phosphoric Monoester Hydrolases; Physicians; Plague; Play; Population; Positioning Attribute; Prevalence; Process; Production; Proteolysis; Public Health; Publications; Regulation; Research; Residencies; Resources; Rheumatology; Role; Scientist; Signal Pathway; Signal Transduction; Societies; Statistical Data Interpretation; T-Lymphocyte; TREM2 gene; TYROBP gene; Techniques; Thinness; Time; Training; Translations; Universities; Work; adipocyte differentiation; alpha secretase; attenuation; career; cell type; clinical practice; college; cytokine; gamma secretase; in vitro testing; inflammatory milieu; inhibitor/antagonist; insulin sensitivity; knock-down; macrophage; notch protein; novel; pediatric department; professor; protein expression; protein protein interaction; recruit; secretase; skills; statistics; symposium; tool

Abstract The candidate, David P. Sparling, MD, PhD, proposes a Clinical Scientist Development Award project as a means to achieve his goal of becoming an independent physician scientist studying the regulation of adipose tissue and inflammation in obesity and Type 2 diabetes mellitus (T2DM). While much effort has been put into understanding the role of inflammatory cells, e.g. macrophages and T cells, in the progression of adipose tissue insulin resistance, there should also be a focus on the cell likely originating those inflammatory signals—namely, the adipocyte. A variety of signaling events likely occur during the inflammatory processes in excessive adiposity, and a novel tool has been implicated to study these processes: the -secretase enzyme complex. Signaling cascades regulating both adipose differentiation and insulin sensitivity cascades utilize -secretase, and it plays a role in several immune signaling cascades in other cell types. However, the function of-secretase in adipocyte-initiated inflammatory signaling is unknown. Dr. Sparling proposes that -secretase blockade could be a tool to identify novel cascades and signaling functions in adipocyte inflammation. Preliminary data has suggested that adipocyte-specific blockade of -secretase alters the inflammatory milieu of lean and obese adipose tissue. Dr. Sparling hypothesizes that -secretase is integral to adipocyte-initiated inflammatory signaling cascades, and that this hypothesis can be tested in vitro with two specific aims. Aim 1 will determine if -secretase is required for adipocyte-initiated macrophage recruitment and activation, and Aim 2 will determine if the immunoreceptor TREM2 in adipocytes is regulated in a -secretase dependent manner. Dr. Sparling will first identify the role of adipocyte -secretase in recruitment and activation of macrophages. He will identify changes in established inflammatory cytokines MCP1 and IL6 secreted by adipocytes following -secretase inhibition. He will also explore novel targets of -secretase regulated intramembrane proteolysis that play a role in adipocyte inflammation. He will then examine the alterations in TREM2 signaling following -secretase inhibition. TREM2 is a known -secretase target in immune cells, and can regulate adipose function. He will determine if -secretase inhibition alters TREM2 protein-protein interactions and downstream signaling in adipocytes. In the long term, this work seeks to establish how adipocytes regulate inflammatory signals in the progression of obesity to T2DM. Dr. Sparling has shown a lasting commitment to basic research and its possible translation to clinical practice. His dissertation at the University of Oklahoma was on the transcriptional regulatory mechanisms of the insulin-responsive glucose transporter GLUT4. After pediatrics residency at Columbia University he completed a fellowship in pediatric endocrinology, studying the role of the Notch cascade in developed adipose tissue. This work was funded by the Endocrine Fellows Foundation and the Pediatric Endocrine Society, and resulted in a first author publication. He accepted his position as an Assistant Professor at the University of Oklahoma Health Sciences Center, Department of Pediatrics, in the Section of Pediatric Diabetes and Endocrinology, where he now has protected time to begin his research career. The basis of Dr. Sparling's work has been in adipose biology, but has now expanded to focus on inflammatory signaling. As such, training gaps for Dr. Sparling have been identified: his understanding of immune cell function and inflammatory regulators, as well as a need for better understanding of appropriate techniques in advanced data analysis. To reach his goal as an independent clinician scientist studying adipose inflammation, these gaps must be addressed. The K08 award provides an excellent means to achieve these goals. During the award Dr. Sparling will: 1) Expand his understanding of the immune system and inflammatory signaling cascades. This will primarily be through instruction and training by his mentor, Dr. Mary Beth Humphrey, chair of the Division of Rheumatology, Immunology, and Allergy in the Department of Medicine at OUHSC. He will also attend graduate didactic courses in immunology, as well as immunology research conferences on campus. 2) Acquire advanced training in statistical analysis through additional statistics courses offered through the Department of Biostatistics and Epidemiology in the College of Public Health at OUHSC. Obesity continues to plague both pediatric and adult populations, and inflammation can play a role in insulin resistance. What is not fully known is what degree inflammation is initiated directly by the adipocyte, and how that signaling evolves in the progression to T2DM. The goal of this award is to develop the skills to examine how inflammatory signals effect cross-talk between adipocytes and the immune system. The environment at the University of Oklahoma is well suited for this work, with mentors, collaborators, and resources all available to successfully complete this project. The training afforded by this award will prepare Dr. Sparling to seek ongoing extramural funding to continue to contribute to the field of diabetes and endocrinology.

抽象的 候选人，医学博士David P. Sparling，提议临床科学家发展奖项项目作为一种手段 为了实现他成为研究脂肪组织调节和的独立物理科学家的目标 肥胖和2型糖尿病（T2DM）的炎症。尽管已经付出了很多努力来理解角色 炎性细胞，例如巨噬细胞和T细胞，在脂肪组织胰岛素耐药性的进展中，应 还要关注可能源自这些炎症信号的细胞，即脂肪细胞。多种信号传导 炎症过程中可能发生的事件可能过多地肥胖，并且已经暗示了一种新的工具来研究 这些过程：-分泌酶复合物。信号级联调节脂肪分化和胰岛素 灵敏度级联反应利用-分泌酶，并且在其他细胞类型的几种免疫信号级联反应中起作用。 但是，-分泌酶在脂肪细胞引起的炎症信号传导中的功能尚不清楚。 Sparling博士的提议 -分泌酶阻断可能是识别脂肪细胞注射中新型级联反应和信号传导功能的工具。 初步数据表明，-分泌酶的脂肪细胞特异性封锁改变了瘦的炎症环境 肥胖的脂肪组织。 Sparling博士假设-分泌酶是脂肪细胞引起的炎症信号级联反应不可或缺的 并且该假设可以通过两个具体的目的在体外检验。 AIM 1将确定是否需要-分泌酶 脂肪细胞引起的巨噬细胞募集和激活，AIM 2将确定免疫受体trem2是否在 脂肪细胞以分泌酶依赖性方式进行调节。 Sparling博士将首先确定脂肪细胞的作用-分泌酶 在招募和激活巨噬细胞中。他将确定已建立炎症性细胞因子MCP1和 -分泌酶抑制后由脂肪细胞分泌的IL6。他还将探索受调节酶调节酶的新靶标 膜内蛋白水解在脂肪细胞注射中起作用。然后，他将检查trem2的变化2 -分泌酶抑制后的信号传导。 TREM2是免疫细胞中已知的-分泌酶靶标，可以调节脂肪 功能。他将确定-分泌酶抑制是否改变了Trem2蛋白 - 蛋白质相互作用和下游信号传导 在脂肪细胞中。从长远来看，这项工作旨在确定脂肪细胞如何调节炎症信号 肥胖向T2DM的进展。 Sparling博士对基础研究及其可能转化为临床实践表现出了持久的承诺。他的 俄克拉荷马大学的论文是关于胰岛素反应性的转录调节机制 葡萄糖转运蛋白GLUT4。在哥伦比亚大学的儿科住所后，他完成了小儿研究金 内分泌学，研究Notch Cascade在发达的脂肪组织中的作用。这项工作由内分泌资助 研究员基金会和小儿内分泌学会，并导致了第一篇作者出版物。他接受了自己的位置 作为儿科系俄克拉荷马大学健康科学中心的助理教授， 小儿糖尿病和内分泌学，他现在已经保护了开始他的研究生涯的时间。 Sparling博士的工作的基础是脂肪生物学，但现在已经扩展到专注于炎症 信号。因此，已经确定了用于Sparling博士的培训差距：他对免疫细胞功能的理解和 炎症调节剂，以及在高级数据分析中更好地理解适当技术的需求。 为了实现他作为研究脂肪注射的独立临床科学家的目标，必须解决这些差距。这 K08奖提供了实现这些目标的绝佳手段。在奖励中，Sparling博士将： 1）扩展他对免疫系统和炎症信号级联的理解。这将是主要的 通过他的导师玛丽·贝丝·汉弗莱（Mary Beth Humphrey）博士的指导和培训 OUHSC医学系中的风湿病，免疫学和过敏。他也会参加 校园的免疫学和免疫学研究会议的研究生教学课程。 2）通过通过其他统计课程获得统计分析的高级培训 OUHSC公共卫生学院生物统计学和流行病学系。 肥胖症继续困扰小儿和成人种群，炎症可以在胰岛素中发挥作用 反抗。尚不完全了解的是脂肪细胞直接引发了什么程度的炎症，以及如何直接发起炎症 向T2DM进展中的信号演变。该奖项的目的是发展技能，以研究如何炎症 信号影响脂肪细胞和免疫系统之间的串扰。俄克拉荷马大学的环境是 非常适合这项工作，具有心态，合作者和资源，所有这些都可以成功完成该项目。 该奖项提供的培训将为Sparling博士做好准备，以寻求正在进行的校外资金，以继续贡献 到糖尿病和内分泌学领域。