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HYPOGLYCEMIA-ASSOCIATED AUTONOMIC FAILURE AND THE BRAIN

低血糖相关的自主神经衰竭和大脑

基本信息

批准号：
6634766
负责人：
NANCY C TKACS
金额：
$ 11.06万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-15 至 2005-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant) Long term complications of diabetes are reduced in patients with tightly controlled plasma glucose levels. A frequent consequence of this tight control is severe hypoglycemia. Recurrent hypoglycemia leads to hypoglycemia-associated autonomic failure and unawareness, through mechanisms that are not well understood at this time. This proposal describes a rodent model of reduced sympathoadrenal activation after hypoglycemia. Brain changes observed in this model include evidence of neuronal apoptosis and changes in peptide gene expression in the arcuate nucleus of the hypothalamus. The experiments proposed here investigate the role of the arcuate nucleus in responses to hypoglycemia. Phenotyping arcuate neurons activated by hypoglycemia will be done by combining Fos immunohistochemistry with in situ hybridization for neuropeptide Y, pro-opiomelanocortin, glutamic acid decarboxylase and glucokinase. The role of brain hypoglycemia in endocrine and Fos responses to hypoglycemia will be assessed using systemic insulin combined with brain glucose infusions. Recovery of normal counter regulation and arcuate gene expression after hypoglycemia will be evaluated using physiological measures, in situ hybridization, Northern blots, and RT-PCR. The results of this research will provide fundamental information about the neuroanatomy of the counterregulatory response and the brain alterations after recurrent hypoglycemia that dangerously reduce the organism' s ability to respond to this important biological signal. The principle investigator is a master's prepared nurse with doctoral training in physiology, postdoctoral training in neuroendocrinology, and independent research experience investigating the functional neuroanatomy of brain responses to peripheral immune stimulation. She now seeks to broaden her research focus to study central nervous system integration of responses to hypoglycemia, a growing problem in patients with intensive treatment of type I diabetes mellitus. Since long-term changes in responsiveness to hypoglycemia are likely to involve changes in gene expression, the Principal Investigator seeks mentored development of her research skills in the area of molecular neurobiology. The University of Pennsylvania School of Nursing is a top-ranked academic nursing center, and is highly ranked in quantity and quality of its sponsored research programs. The University of Pennsylvania has a nationally funded Diabetes Endocrinology Research Center, and an active Institute of Neurological Sciences. The research plan, candidate, and environment are well-suited for an ongoing career in fundamental diabetes research.

描述（由申请人提供）糖尿病患者的长期并发症减少，控制血糖水平。这种严格控制的常见后果是，是严重的低血糖复发性低血糖导致低血糖相关性自主故障和无意识，通过机制，在这个时候理解。该提案描述了一种减少的啮齿动物模型，低血糖后交感肾上腺激活。在这一过程中观察到的大脑变化模型包括神经元凋亡和肽基因变化的证据表达于下丘脑弓状核。提出的实验在此研究弓状核在低血糖反应中的作用。低血糖激活的弓状神经元的表型将通过结合 Fos免疫组织化学原位杂交检测神经肽Y，阿黑皮素原、谷氨酸脱羧酶和葡糖激酶。的作用脑内分泌低血糖和Fos对低血糖的反应将是使用全身胰岛素联合脑葡萄糖输注进行评估。恢复低血糖后正常的反调节和弓形基因表达将使用生理学测量、原位杂交、北方印迹和RT-PCR。这项研究的结果将提供基本的关于反调节反应的神经解剖学信息，反复低血糖后的大脑改变，生物体对这种重要的生物信号作出反应的能力。主要研究者是一名经过博士培训的硕士护士在生理学，神经内分泌学博士后培训，并独立脑功能神经解剖学研究经验对外周免疫刺激的反应。她现在试图扩大她的研究重点是研究中枢神经系统的整合反应，低血糖，I型糖尿病强化治疗患者日益严重的问题糖尿病的由于对低血糖反应性的长期变化可能涉及基因表达的变化，首席研究员寻求她在分子生物学领域的研究技能的指导发展神经生物学宾夕法尼亚大学护理学院是一个排名靠前的学术护理中心，并在其数量和质量方面排名靠前赞助的研究项目。宾夕法尼亚大学在全国范围内资助的糖尿病内分泌研究中心，和一个活跃的研究所，神经科学。研究计划、候选人和环境是非常适合基础糖尿病研究的持续职业生涯。