HYPOGLYCEMIA-ASSOCIATED AUTONOMIC FAILURE AND THE BRAIN

描述(由申请人提供) 糖尿病患者的长期并发症明显减少 控制血糖水平。这种严格控制的常见后果 是严重的低血糖。反复低血糖导致低血糖相关 自主失灵和无意识，通过不太好的机制 我现在明白了。本提案描述了一种简化的啮齿动物模型。 低血糖后交感神经肾上腺的激活。在此过程中观察到的大脑变化 模型包括神经细胞凋亡和多肽基因变化的证据 在下丘脑的弓状核有表达。建议进行的实验 这里研究弓状核在低血糖反应中的作用。 由低血糖激活的弓状神经元表型将通过结合 神经肽Y的FOS免疫组织化学原位杂交， 前阿片黑素皮质素、谷氨酸脱羧酶和葡萄糖激酶。的作用 脑内分泌低血糖和Fos对低血糖的反应 使用全身胰岛素结合脑部葡萄糖输注进行评估。恢复 低血糖后正常逆调节和弓形基因表达的变化 将使用生理指标、原位杂交、Northern进行评估 Blotts和RT-PCR。这项研究的结果将为我们提供基础 关于反调节反应的神经解剖学信息和 反复低血糖后的脑改变，危险地降低了 生物体S对这一重要生物信号的反应能力。 首席调查员是一名经过博士培训的硕士护士 在生理学、博士后、神经内分泌学方面进行培训，并独立完成 脑功能神经解剖学的研究体会 对外周免疫刺激的反应。她现在寻求扩大她的 中枢神经系统整合反应的研究重点 低血糖，I型强化治疗患者日益严重的问题 糖尿病。由于对低血糖反应性的长期变化 很可能涉及基因表达的变化，首席调查员 寻求在指导下发展她在分子领域的研究技能 神经生物学。宾夕法尼亚大学护理学院是一流的 学术护理中心，在护理服务的数量和质量上都名列前茅 赞助的研究项目。宾夕法尼亚大学有一个全国性的 资助的糖尿病内分泌学研究中心和一个活跃的 神经科学。研究计划、候选人和环境如下 非常适合从事基础糖尿病研究。

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.