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Targeting intracellular calcium leak as novel therapy for diabetes

针对细胞内钙渗漏作为糖尿病的新疗法

基本信息

批准号：
9144395
负责人：
Gaetano Santulli
金额：
$ 8.82万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-14 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9144395
关键词：
Acquaintances Address Adverse effects Affect Animal Model Area Award Beta Cell Binding Biomedical Research Biometry Budgets Calcium Catecholaminergic Polymorphic Ventricular Tachycardia Cell membrane Cell physiology Clinical Trials Complex DNA Sequence Alteration Data Development Diabetes Mellitus Disease Drug Targeting Education Endoplasmic Reticulum Environment Experimental Designs Extracellular Space FKBP1B gene Factor Analysis Foundations Functional disorder Funding Future Genetic Glucose Glucose Intolerance Goals Grant Health Heart Diseases Homeostasis Human Human Resources In Vitro Insulin International Intervention Ion Channel Islets of Langerhans Knock-in Mouse Knowledge Laboratories Lead Link Macromolecular Complexes Mentors Meta-Analysis Metabolic Metabolism Methods Minor Mitochondria Modeling Modification Molecular Mus Mutate Mutation Myopathy Non-Insulin-Dependent Diabetes Mellitus Obese Mice Outcome Patients Phase Phase Transition Play Positioning Attribute Prevention Principal Investigator Production Public Health Reporting Research Role RyR2 Ryanodine Receptors Scientist Signal Transduction Structure of beta Cell of islet Syndrome Tachycardia Techniques Testing Therapeutic Training Universities Work Writing base biological adaptation to stress blood glucose regulation career design endoplasmic reticulum stress falls glucose metabolism glucose tolerance high throughput analysis human subject protection improved in vivo innovation insulin secretion insulin sensitivity islet meetings mitochondrial dysfunction mitochondrial fitness molecular targeted therapies mouse model new therapeutic target notch protein novel novel strategies novel therapeutic intervention novel therapeutics prevent release of sequestered calcium ion into cytoplasm research study response responsible research conduct skills small molecule targeted treatment tool treatment strategy voltage volunteer

项目摘要

DESCRIPTION (provided by applicant): The proposed research study will facilitate the improvement of the education and career goals of the principal investigator (PI). Moreover, the candidate will investigate the mechanisms that underlie impaired insulin secretion in type 2 diabetes mellitus (T2DM). The candidate has set up an important educative plan for the first two years (K99 phase) of the proposed study. This plan includes also courses. In addition, the candidate will be trained in scientific and professional research skills by his mentors and other experts. The candidate will perform experiments to investigate the molecular mechanisms underlying the functional role of intracellular calcium leak in the pathophysiology of T2DM and will suggest innovative, targeted therapeutic approaches for the treatment of such a disease. Upon conclusion of the mentored phase the candidate will have established a pool of data, knowledge and scientific skills that will enhance his credentials for successful transition to independence. During the K99 phase the candidate has planned to attend courses on biostatistics, grant writing/research funding, human subject protection, and responsible conduct of research. In addition, he has set up a specific training plan with his mentors and his advisors/collaborators that will provide him with scientific knowledge on ER stress/mitochondrial fitness, β-cell dynamics, ion channels. These aspects represent useful tools that he will be able to transfer to his own laboratory. Besides the new techniques that he will acquire, the proposed project requires knowledge in areas that he has only recently been associated with, such as mitochondrial pathophysiology and metabolic signaling. Therefore, he has included in his advisory board a number of scientists with outstanding careers in these particular fields that will provide guidance of the highest possible level. All his advisors and collaborators are top-notch academic scientists (see a complete list in Personnel, in the `Budget justification' document). The candidate will also present his work at several international meetings, in order to receive input by a broad scientific audience, thereby expanding his scientific network. This will promote his transition to an independent research position and provide him a robust scientific foundation from which to apply for independent R01-level funding. The application core questions are: (1) Which is the functional role of intracellular Ca2+ leak via RyR2 in pancreatic β-cells? (2) What i the mechanism underlying impaired glucose-stimulated insulin secretion in β-cells harboring leaky RyR2 channels? (3) How can the leak be prevented in human islets from T2DM donors or animal models of diabetes? (4) How the prevention of intracellular Ca2+ leak can impact the pathophysiology of T2DM? To address these questions the candidate has designed an experimental plan with two main branches. The first falls into the K99 phase and is based on preliminary data of the current submission. This set of experiments aims to identify the mechanism that makes the Ca2+ leak via RyR2 channels in β-cells a heretofore undisclosed key player in glucose-induced insulin release. The applicant will characterize both in vivo and ex vivo the functional aspects of leaky RyR2 using knock-in mice harboring genetic mutations in RyR2 that renders the channel leaky. The same mutations characterize a rare syndrome, known as catecholaminergic polymorphic ventricular tachycardia (CPVT); intriguingly, studies provided as material supporting the present application have demonstrated that most of these patients display glucose intolerance. The candidate will verify the effects of the induction of the leak in vitro on insulin release. Moreover, he will test an orally available small molecule (Rycal) in the CPVT mouse models, to see whether such pharmacological intervention, able to prevent intracellular Ca2+ leak, can affect β-cell dynamics. The second branch of the plan falls into the R00 phase, where the candidate will determine whether the inhibition of intracellular Ca2+ leak via RyR2 improves glucose homeostasis in established models of T2DM. These models will be characterized with high throughput analysis methods and new targets may come up. Equally important, the elucidation of the mechanisms that will be investigated in the K99 phase (ER stress, mitochondria, ion channels) might also identify new targets and may suggest novel approaches for the treatment of T2DM. Ultimately, application of these strategies and interventions, as well as targeting of new factors that the analysis focused on ER Stress and Ca2+ fluxes is most likely going to indicate new directions to treat conditions of impaired glucose homeostasis. Moreover, with the scientific and professional skills acquired by the applicant during the K99 phase, the transition to independent position will be certainly facilitate. Overall, the current application will equip the candidate with novel knowledge and useful tools to continue for independent career in molecular metabolism and diabetes research. His training plan has been meticulously designed to facilitate flawless production of data in the prominent environment of Columbia University, as well as the PI's acquaintance with modern tools of biomedical research that he will transfer to his independent laboratory. Approval of his application for the K99/R00 award will result in the precise definition of novel mechanisms affecting β-cell pathophysiology, challenging current paradigms and will thereby provide potential new therapeutics for the treatment of diabetes mellitus.

描述（由申请人提供）：拟议的研究将有助于改善主要研究者（PI）的教育和职业目标。此外，候选人还将研究 2 型糖尿病 (T2DM) 中胰岛素分泌受损的机制。候选人已为拟议学习的前两年（K99 阶段）制定了重要的教育计划。该计划还包括课程。此外，候选人还将接受导师和其他专家的科学和专业研究技能培训。候选人将进行实验来研究细胞内钙渗漏在 T2DM 病理生理学中功能作用的分子机制，并为治疗此类疾病提出创新的、有针对性的治疗方法。指导阶段结束后，候选人将建立一个数据、知识和科学技能库，这将增强他成功过渡到独立的资格。在 K99 阶段，候选人计划参加生物统计学、拨款写作/研究资助、人类受试者保护和负责任的研究行为等课程。此外，他还与导师和顾问/合作者制定了具体的培训计划，为他提供有关内质网应激/线粒体适应性、β细胞动力学、离子通道的科学知识。这些方面代表了有用的工具，他将能够将其转移到自己的实验室。除了他将获得的新技术之外，拟议的项目还需要他最近才涉足的领域的知识，例如线粒体病理生理学和代谢信号传导。因此，他的顾问委员会中包括了一些在这些特定领域具有杰出职业生涯的科学家，这些科学家将提供尽可能最高水平的指导。他的所有顾问和合作者都是顶尖的学术科学家（请参阅“人事”中“预算合理性”文件中的完整列表）。该候选人还将在几次国际会议上展示他的工作，以获得广大科学受众的意见，从而扩大他的科学网络。这将促进他向独立研究职位的过渡，并为他申请独立 R01 级资助提供坚实的科学基础。应用核心问题是：（1）胰腺β细胞中通过RyR2的细胞内Ca2+渗漏的功能作用是什么？ (2) 含有泄漏 RyR2 通道的 β 细胞中葡萄糖刺激的胰岛素分泌受损的机制是什么？ (3) 如何预防来自 T2DM 供体或糖尿病动物模型的人类胰岛的渗漏？ (4) 预防细胞内Ca2+渗漏如何影响T2DM的病理生理学？为了解决这些问题，候选人设计了一个有两个主要分支的实验计划。第一个阶段属于 K99 阶段，基于当前提交的初步数据。这组实验旨在确定β细胞中Ca2+通过RyR2通道泄漏的机制，该机制是迄今为止未公开的葡萄糖诱导胰岛素释放的关键因素。申请人将使用 RyR2 中携带导致通道渗漏的基因突变的敲入小鼠，在体内和离体表征渗漏 RyR2 的功能方面。相同的突变是一种罕见综合征的特征，称为儿茶酚胺能多形性室性心动过速（CPVT）；有趣的是，作为支持本申请的材料提供的研究已经证明这些患者中的大多数表现出葡萄糖不耐受。候选人将验证体外诱导渗漏对胰岛素释放的影响。此外，他将在 CPVT 小鼠模型中测试一种口服小分子 (Rycal)，看看这种能够防止细胞内 Ca2+ 渗漏的药物干预是否可以影响 β 细胞动力学。该计划的第二个分支进入 R00 阶段，候选人将确定通过 RyR2 抑制细胞内 Ca2+ 渗漏是否可以改善已建立的 T2DM 模型中的葡萄糖稳态。这些模型将采用高通量分析方法来表征，并且可能会出现新的目标。同样重要的是，阐明 K99 阶段研究的机制（内质网应激、线粒体、离子通道）也可能会确定新的靶标，并可能提出治疗 T2DM 的新方法。最终，这些策略和干预措施的应用，以及针对内质网应激和 Ca2+ 通量分析的新因素，很可能会指明治疗葡萄糖稳态受损状况的新方向。而且，凭借申请人在K99阶段获得的科学和专业技能，向独立职位的过渡肯定会更加容易。总体而言，当前的应用程序将为候选人提供新颖的知识和有用的工具，以继续在分子代谢和糖尿病研究方面的独立职业生涯。他的培训计划经过精心设计，旨在促进在哥伦比亚大学的优越环境中完美地生成数据，以及 PI 熟悉现代生物医学研究工具，并将其转移到他的独立实验室。他申请 K99/R00 奖的批准将导致影响 β 细胞病理生理学的新机制的精确定义，挑战当前的范例，从而为糖尿病的治疗提供潜在的新疗法。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mechanistic Role of MicroRNAs in Coupling Lipid Metabolism and Atherosclerosis.

DOI：
10.1007/978-3-319-22380-3_5
发表时间：
2015
期刊：
Advances in experimental medicine and biology
影响因子：
0
作者：
Novák J;Olejníčková V;Tkáčová N;Santulli G
通讯作者：
Santulli G

The Amino-Terminal Domain of GRK5 Inhibits Cardiac Hypertrophy through the Regulation of Calcium-Calmodulin Dependent Transcription Factors.

DOI：
10.3390/ijms19030861
发表时间：
2018-03-15
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Sorriento D;Santulli G;Ciccarelli M;Maione AS;Illario M;Trimarco B;Iaccarino G
通讯作者：
Iaccarino G

microRNAs Distinctively Regulate Vascular Smooth Muscle and Endothelial Cells: Functional Implications in Angiogenesis, Atherosclerosis, and In-Stent Restenosis.

DOI：
10.1007/978-3-319-22380-3_4
发表时间：
2015
期刊：
Advances in experimental medicine and biology
影响因子：
0
作者：
Santulli G
通讯作者：
Santulli G

Telemonitoring in heart failure patients treated by cardiac resynchronisation therapy with defibrillator (CRT-D): the TELECART Study.

DOI：
10.1111/ijcp.12823
发表时间：
2016-07
期刊：
International journal of clinical practice
影响因子：
2.6
作者：
Sardu C;Santamaria M;Rizzo MR;Barbieri M;di Marino M;Paolisso G;Santulli G;Marfella R
通讯作者：
Marfella R

Overlooking cardiac dysfunction triggered by immune checkpoint inhibitors: Caution, trespassers will be ventilated.

忽视免疫检查点抑制剂引发的心脏功能障碍：小心，侵入者将被通气。