Function of the hypothalamic melanocortin system in stimulating counter-regulatory response to hypoglycemia
下丘脑黑皮质素系统在刺激低血糖反调节反应中的功能
基本信息
- 批准号:9295097
- 负责人:
- 金额:$ 10.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2021-03-31
- 项目状态:已结题
- 来源:
- 关键词:AgonistBlood GlucoseBrainCessation of lifeClosure by clampConfusionDataDiabetes MellitusDoctor of PhilosophyEducationEpinephrineExhibitsFutureGeneticGlucagonGlucoseGoalsGrantHormonesHypoglycemiaHypothalamic structureImmunohistochemistryImpairmentIn Situ HybridizationInstitutionInsulinKnockout MiceKnowledgeLifeMelanocortin 4 ReceptorMentored Research Scientist Development AwardMentorsMichiganMusNeuraxisNeuroanatomyNeuropharmacologyOrganOutcomePathway interactionsPatientsPeripheralPharmaceutical PreparationsPhysiologicalPostdoctoral FellowPreventionPro-OpiomelanocortinQuality of lifeResearchResearch PersonnelRoleScientistSeizuresStreptozocinStructure of nucleus infundibularis hypothalamiSympathetic Nervous SystemSystemTechniquesTestingTrainingTransgenic MiceUnconscious StateUniversitiesblood glucose regulationcareercounterregulationexperiencefightinghigh riskimprovedinsightinsulin secretionmouse modelparaventricular nucleuspost-doctoral trainingpreventpublic health relevanceresponseskillstool
项目摘要
The primary goal of this K01 award application is to acquire necessary training and research experience to facilitate my
transition to an independent research career. So far in my postdoctoral training, I have applied my skills and knowledge
that were learned during my PhD education in Dr. Eric Lazartigues' lab. Moving forward, I would like to acquire new
research skills and develop a project that is different from Dr. Malcolm Low's (my postdoc mentor) ongoing research. I
would like to integrate my current skills in studying peripheral organs with new techniques pertaining to the central
nervous system. I will undertake training and courses in neuropharmacology, neuroanatomy, developing transgenic mouse
models employing opto- and pharmaco- genetic tools. My long term career goal is to become an independent investigator
at a major academic research-focused institution and to contribute toward our understanding of the function of brain in
glucose homeostasis. Patients with both type 1 and type 2 (late stage) diabetes are at high risk of facing life-threating
hypoglycemia due to tight glucose control therapy. Normally, hormones such as epinephrine and glucagon are released to
counteract hypoglycemia; however, patients with diabetes exhibit impaired counter-regulatory response to hypoglycemia.
Consequently, the function of brain deteriorates due to lack of glucose and these patients may experience confusion,
seizures, unconsciousness, and death if not treated immediately. During K01 award period, I aim to determine the central
pathways involved in hypoglycemia counter-regulation. My preliminary data suggest that hypothalamic melanocortin
system is essential in counteracting hypoglycemia. Arcuate nucleus-specific Pomc knockout mice (ArcPomc-/-) exhibit
impaired response to glucose deficit. Therefore, in Aim 1, I will determine a physiological role of hypothalamic POMC in
counteracting hypoglycemia. I will employ immunohistochemistry, in situ hybridization, and hypoglycemic clamps to
accomplish Aim 1. I have observed that melanocortin 4 receptor (MC4R) agonist treatment improves, while its antagonist
worsens, the counter-regulatory response in ArcPomc-/- and WT mice, respectively. Hence, Aim 2 of this project is to
examine the function of the MC4R specifically in the paraventricular nucleus of the hypothalamus (PVH, a region that
regulates sympathetic nervous system activity) in stimulating counter-regulatory response to hypoglycemia. I will employ
opto- and pharmaco- genetic tools to elucidate the role of MC4RPVH in hypoglycemia counter-regulation. Finally, in Aim
3, I will examine the impact of diabetes on hypothalamic POMC and MC4R levels to ascertain the mechanism underlying
reduced response to hypoglycemia during diabetes. Moreover, I will test the potential of MC4R agonist in preventing life-
threatening hypoglycemia in streptozotocin (STZ) treated mice with diabetes. The outcome of this project will have direct
implication for prevention of fatal hypoglycemic episodes in patients with diabetes. Importantly, with the progress of this
project, I will be able to acquire expertise in the aforementioned techniques, and generate data for future studies and
applications for R03 and R01 grants. My mentoring committee includes a number of scientists, with outstanding careers,
that will provide guidance of the highest possible level for all of the aims of this project. The University of Michigan
along with its Diabetes Research Center will provide me an excellent facility to successfully complete my project.
本次K01奖项申请的主要目的是获得必要的培训和研究经验,以促进我的研究
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Kavaljit H Chhabra其他文献
Kavaljit H Chhabra的其他文献
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{{ truncateString('Kavaljit H Chhabra', 18)}}的其他基金
Role of hypothalamic MC4R in glucose homeostasis via a novel neuroendocrine circuit involving the kidneys and adrenal glands
下丘脑 MC4R 通过涉及肾脏和肾上腺的新型神经内分泌回路在葡萄糖稳态中的作用
- 批准号:
10454300 - 财政年份:2021
- 资助金额:
$ 10.11万 - 项目类别:
Role of hypothalamic MC4R in glucose homeostasis via a novel neuroendocrine circuit involving the kidneys and adrenal glands
下丘脑 MC4R 通过涉及肾脏和肾上腺的新型神经内分泌回路在葡萄糖稳态中的作用
- 批准号:
10666539 - 财政年份:2021
- 资助金额:
$ 10.11万 - 项目类别:
Role of hypothalamic MC4R in glucose homeostasis via a novel neuroendocrine circuit involving the kidneys and adrenal glands
下丘脑 MC4R 通过涉及肾脏和肾上腺的新型神经内分泌回路在葡萄糖稳态中的作用
- 批准号:
10296199 - 财政年份:2021
- 资助金额:
$ 10.11万 - 项目类别:
Role of hypothalamic MC4R in glucose homeostasis via a novel neuroendocrine circuit involving the kidneys and adrenal glands
下丘脑 MC4R 通过涉及肾脏和肾上腺的新型神经内分泌回路在葡萄糖稳态中的作用
- 批准号:
10854123 - 财政年份:2021
- 资助金额:
$ 10.11万 - 项目类别:
Prevention of hypoglycemia associated autonomic failure by enhancing melanocortin 4 receptor function
通过增强黑皮质素 4 受体功能预防低血糖相关的自主神经衰竭
- 批准号:
9807544 - 财政年份:2019
- 资助金额:
$ 10.11万 - 项目类别:
FUNCTION OF THE HYPOTHALAMIC MELANOCORTIN SYSTEM IN STIMULATING COUNTER-REGULATORY RESPONSE TO HYPOGLYCEMIA
下丘脑黑皮质素系统刺激低血糖反调节反应的功能
- 批准号:
9897600 - 财政年份:2017
- 资助金额:
$ 10.11万 - 项目类别:
FUNCTION OF THE HYPOTHALAMIC MELANOCORTIN SYSTEM IN STIMULATING COUNTER-REGULATORY RESPONSE TO HYPOGLYCEMIA
下丘脑黑皮质素系统刺激低血糖反调节反应的功能
- 批准号:
10219651 - 财政年份:2017
- 资助金额:
$ 10.11万 - 项目类别:
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