BLRD Merit Review Research Career Scientist (RCS) Award (IK6)

BLRD 优异评审研究职业科学家 (RCS) 奖 (IK6)

• 批准号: 10618157
• 负责人: Alyssa H Hasty
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 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/10618157
• 关键词: Acceleration; Adipocytes; Adipose tissue; Affect; American Heart Association; Applications Grants; Appointment; Area; Arteriosclerosis; Award; Basic Science; Bioenergetics; Biology; Blood Vessels; Body Weight decreased; Cardiovascular Diseases; Cell Differentiation process; Cells; Committee Members; Data; Development; Diabetes Mellitus; Disease; Endowment; Environment; Epidemic; Etiology; Faculty; Fibrosis; Foundations; Funding; Glucose Intolerance; Grant; Health; Healthcare; Homeostasis; Hour; Human; IACUC; Immune; Immunologic Memory; Immunology; Incidence; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Insulin; Insulin Resistance; International; Investigation; Iron; Journals; Laboratories; Lead; Link; Lipolysis; Macrophage; Manuscripts; Mediating; Medicine; Mentors; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Myelogenous; Natural Immunity; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Paper; Pathway interactions; Peer Review; Phagocytes; Phenotype; Physiology; Population; Postdoctoral Fellow; Prevalence; Privatization; Process; Property; Protocols documentation; Publications; Publishing; Recording of previous events; Research; Research Personnel; Review Committee; Risk; Role; Scientist; Services; T-Lymphocyte; Thinness; Thrombosis; Tissues; Training; United States Department of Veterans Affairs; United States National Institutes of Health; Universities; Veterans; Voting; Weight; Weight Gain; Work; animal care; arm; career; cohort; comorbidity; diabetes risk; early-career faculty; editorial; immune cell infiltrate; indexing; innovation; interest; lipid biosynthesis; medical schools; meetings; member; mid-career faculty; mitochondrial dysfunction; next generation; novel; obesogenic; professor; response; senior faculty; symposium; tenure track

The prevalence of obesity and associated co-morbidities, including type 2 diabetes and cardiovascular disease, has increased dramatically in the past several decades. It is well-established that an immune component contributes to the etiology of metabolic diseases – especially when driven by obesity. For example, nearly all of the immune cells in existence have been shown to reside in adipose tissue (AT). Resident macrophages in AT are thought to contribute to development and proper function of the AT by various homeostatic functions. During weight gain, the numbers and phenotypes of all of the immune cells in AT change such that the overall milieu becomes pro-inflammatory, promoting insulin resistance at the tissue and systemic levels. The Hasty laboratory currently has 2 main areas of investigation in this burgeoning area of immunometabolism: Immunologic memory to weight loss and weight cycling: While weight loss is the ideal approach to reduce the negative metabolic consequences of obesity, it is clear that sustained weight loss is difficult to achieve. Bouts of weight loss followed by subsequent weight-gain lead to “weight-cycling”. Interestingly, several studies in humans demonstrate that weight-cycling increases the risk of developing metabolic diseases. Dr. Hasty and others have published data showing antigenic responses in AT during weight gain. Thus, she has developed the hypothesis that weight-cycling results in a T cell-driven secondary immune response that heightens inflammation in AT, leading to local and systemic insulin resistance (IR). In addition, she has begun to study whether macrophages also “remember” the obesogenic environment in a process called trained innate immunity. This work is funded by her VA Merit Award and by a new Innovation award from the American Heart Association. Macrophage iron handling: Dr. Hasty’s group discovered a novel population of macrophages in AT that are critical for control of local iron concentrations, thereby contributing to adipogenesis and to protection from oxidative stress. Her laboratory’s recent advances offer an excellent opportunity to define a role for resident AT macrophages in iron-related control of AT homeostasis. The intrinsic immunometabolism, i.e. fuel utilization and bioenergetics of the cell, and extrinsic immunometabolism, i.e. secreted products that affect the surrounding tissue environment, are manipulable properties that influence how macrophages contribute to tissue homeostasis. We will determine how iron cycling influences both arms of the immunometabolic role of AT macrophages, thereby influencing systemic insulin action. This work is funded by a new R01. Dr. Hasty has published over 100 peer-reviewed manuscripts in this area in high impact journals including Diabetes, Nature Medicine, Am. J. Physiol. and Mol. Metab. She has always maintained a strong cohort of young scientists within her group, and is keen on training the next generation of immunometabolism experts. Dr. Hasty’s research is highly relevant to Veterans as rates of obesity and metabolic disease are even higher in Veteran’s than in the general civilian population. The work performed by Dr. Hasty and her team are critical for us to better understand immune-mediated mechanisms of obesity-accelerated metabolic disease.

肥胖和相关共病的患病率，包括2型糖尿病和心血管疾病， 在过去的几十年里急剧增加。众所周知，免疫成分 导致代谢性疾病的病因-特别是当由肥胖驱动时。例如，几乎所有 现有的免疫细胞已显示存在于脂肪组织（AT）中。AT中的驻留巨噬细胞 被认为通过各种稳态功能促进AT的发育和正常功能。期间 体重增加，AT中所有免疫细胞的数量和表型发生变化， 变成促炎性的，在组织和全身水平上促进胰岛素抵抗。匆忙的实验室 目前在这个新兴的免疫代谢领域有两个主要的研究领域： 减肥和体重循环的免疫记忆：虽然减肥是减少体重循环的理想方法， 肥胖的负面代谢后果，很明显，持续减肥是难以实现的。发作的 体重减轻，随后体重增加，导致“体重循环”。有趣的是，几项针对人类的研究 研究表明，体重循环会增加患代谢性疾病的风险。哈斯蒂博士和其他人 已发表的数据显示在体重增加期间AT中的抗原应答。因此，她提出了一个假设， 体重循环导致T细胞驱动的二次免疫反应，从而加剧AT的炎症， 导致局部和全身胰岛素抵抗（IR）。此外，她已经开始研究巨噬细胞是否 在一个被称为训练的先天免疫的过程中，也会“记住”致肥环境。这项工作得到了资助 她获得了退伍军人管理局优秀奖和美国心脏协会颁发的新创新奖。 巨噬细胞铁处理：Hasty博士的研究小组在AT中发现了一种新的巨噬细胞群， 对于控制局部铁浓度至关重要，从而有助于脂肪形成和保护 氧化应激她的实验室的最新进展提供了一个极好的机会，以确定一个角色的居民AT 巨噬细胞在铁相关的AT稳态控制。内在免疫代谢，即燃料利用和 细胞的生物能量学和外源性免疫代谢，即影响周围环境的分泌产物。 组织环境，是影响巨噬细胞如何促进组织的可操纵特性 体内平衡我们将确定铁循环如何影响AT的免疫代谢作用 巨噬细胞，从而影响全身胰岛素作用。这项工作由新的R 01资助。 博士Hasty在这一领域的高影响力期刊上发表了100多篇同行评审的手稿，包括 糖尿病，自然医学，美国。和Mol. Metab.她一直保持着一个强大的年轻群体， 她的团队中的科学家，并热衷于培养下一代的免疫代谢专家。Dr. Hasty's 研究与退伍军人高度相关，因为退伍军人的肥胖和代谢疾病率甚至更高。 比一般平民的死亡率高Hasty博士和她的团队所做的工作对我们更好地 了解肥胖加速代谢疾病的免疫介导机制。