Role of the Unfolded Protein Response in Type 2 Diabetes

描述（由申请人提供）： 博士费罗兹河爸爸是一名内分泌学家，坚定地致力于学术生涯作为一个独立的研究人员在（-细胞分子生物学。他特别感兴趣的是内质网（ER）应激在2型糖尿病（DM 2）发展中的作用。因此，他在该部门的Peter Walter博士实验室发起了博士后研究金。他是加州大学旧金山分校生物化学和生物物理学的教授，研究未折叠蛋白反应（UPR），这是一种真核细胞调节ER应激的稳态机制。当在ER腔中经历成熟的客户蛋白质的负荷与ER处理该负荷的能力之间存在不平衡时，发生ER应激。引起内质网应激的病理生理条件包括缺氧、营养缺乏和多肽突变，这些导致蛋白质错误折叠。UPR通过两种机制重塑ER的环境以响应ER应激：1）编码ER分子伴侣、酶活性和结构ER组分的基因的转录上调，和2）整体翻译停止，其减少ER客户蛋白的负荷。ER-跨膜激酶/核糖核酸内切酶Ire 1 alpha是UPR转录臂的传感器，ER-跨膜elF-2 alpha激酶Perk是翻译臂的传感器。Papa博士提出了一项研究计划，该计划将解决调节UPR的假设，在真实的时间使用小分子效应器，可以影响β细胞的功能，并最终影响其生存。他将通过三个具体目标来阐述这一假设。首先，使用化学遗传策略，他将通过将IRE 1alpha基因靶向于细胞可渗透的ATP类似物1-NM PP 1来敏化Ire 1alpha，他已经证明了1-NM PP 1是酵母中敏化Ire 1的信号传导的允许辅助因子。β细胞特异性基因靶向将使该组织在1 NM-PP 1不存在的情况下不能向UPR的转录臂发出信号。其次，将进行PERK的类似基因靶向，从而赋予UPR的翻译臂药理学条件。第三，将在这些敲入突变体中，以及在由于未受抑制的ER应激而产生DM 2的三种其他小鼠突变体的遗传背景中研究这些操作对β细胞的生物学后果：秋田、hlAPP和perk-/-。总之，这项工作有望产生重要的见解专业分泌组织（包括但不限于β细胞）如何适应生理和病理生理压力。Papa博士将在本部门开展这项工作。生物化学和生物物理在加州大学旧金山分校的指导下，博士彼得沃尔特，并与博士罗伯特Farese，小合作。格莱斯顿心血管疾病研究所的博士，以及细胞和分子药理学系的凯文·肖卡特博士。UCSF医学系完全致力于Papa博士的职业发展，并将提供所有必要的资源，以促进该项目的成功。

DESCRIPTION (provided by applicant): Dr. Feroz R. Papa is an endocrinologist, strongly committed to an academic career as an independent investigator in (-cell molecular biology. His specific interest is the role of endoplasmic reticulum (ER) stress in development of diabetes mellitus type 2 (DM2). Accordingly, he has initiated a postdoctoral fellowship in the lab of Dr. Peter Walter, in the Dept. of Biochemistry and Biophysics at UCSF, studying the Unfolded Protein Response (UPR), a homeostatic mechanism through which eukaryotic cells adjust to ER stress. ER stress occurs when there is an imbalance between the load of client proteins undergoing maturation in the ER lumen and the capacity of the ER to process this load. Pathophysiological conditions provoking ER stress include anoxia, nutrient deprivation, and polypeptide mutations, which result in protein misfolding. The UPR remodels the environment of the ER to respond to ER stress through two mechanisms: 1) a transcriptional upregulation of genes encoding ER chaperones, enzymatic activities, and structural ER components, and 2) a global translational halt, which reduces the load of ER client proteins. The ER-transmembrane kinase/endoribonuclease Ire1alpha is the sensor for the transcriptional arm of the UPR, and the ER-transmembrane elF-2alpha kinase Perk is the sensor for the translational arm. Dr. Papa is proposing a research program which will address the hypothesis that modulating the UPR, in real time using small molecule effectors, can influence the function of beta-cells, and ultimately their survival. He will address this hypothesis through three specific aims. First, using a chemical-genetic strategy, he will sensitize Ire1alpha by gene targeting of IRE1alpha to a cell-permeable ATP analog, 1-NM PP1, which he has demonstrated is a permissive co-factor for signaling by sensitized Ire1 in yeast. Beta-cell-specific gene targeting would render this tissue unable to signal the transcriptional arm of the UPR in the absence of 1NM-PP1 Second, similar gene targeting of PERK will be conducted, conferring pharmacological conditionality on the translational arm of the UPR. Third, the biological consequences of these manipulations on beta-cells will be studied in these knock-in mutants, and in the genetic background of three other mouse mutants which develop DM2 as a consequence of unchecked ER stress: Akita, hlAPP, and perk-/-. Together this work promises to yield important insights into how professional secretory tissues (including, but not limited to beta-cells) adapt to physiological and pathophysiological stresses. Dr. Papa will conduct this work in the Dept. of Biochemistry and Biophysics at UCSF under the mentorship of Dr. Peter Walter, and in collaboration with Dr. Robert Farese, Jr. in the Gladstone Institute of Cardiovascular Disease, and Dr. Kevan Shokat in the Department of Cellular and Molecular Pharmacology. The UCSF Department of Medicine is fully committed to Dr. Papa's career development, and will make all necessary resources available to facilitate the success of the project.