Guided by the notion that late onset chronic diseases are the consequence of prolonged overworking of various tissues that have genetic and epigenetic vulnerabilities, I assert that it is the cellular energy metabolism of the different tissues that determines their health and longevity and consequently that of the entire organism. Based on my previous and ongoing work, I hypothesize that a small set of neurons in the hypothalamus, which produce Agouti-related protein (AgRP), act as the master regulator of energy utilization by all tissues, and hence, these hypothalamic neurons determine healthy tissue function and longevity. We will selectively up- or down-regulate the activity of hypothalamic AgRP neurons and test the effect of these perturbations on normal physiology of peripheral tissues and that of the brain. I suggest that these changes in peripheral tissue function by altered AgRP neuronal functioning will have critical impact on higher brain functions as well, including learning and memory and the ability of the brain to withstand stress during neurodegeneration induced either by normal aging or by pathological processes, such as Alzheimer?s and Parkinson?s disease. This project is uniquely suited for the NDPA program because it is unconventional and represents an approach in biomedical research that is nonexistent. It is a high risk avenue, but, if successful, would have great benefits in that it could immediately lead to novel treatments for various chronic diseases.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1OD006850-02
Application #
8145621
Study Section
Special Emphasis Panel (ZGM1-NDPA-B (01))
Program Officer
Wehrle, Janna P
Project Start
2010-09-30
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$819,431
Indirect Cost
Name
Yale University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Dietrich, Marcelo O; Zimmer, Marcelo R; Bober, Jeremy et al. (2015) Hypothalamic Agrp neurons drive stereotypic behaviors beyond feeding. Cell 160:1222-32
Scafidi, Joseph; Hammond, Timothy R; Scafidi, Susanna et al. (2014) Intranasal epidermal growth factor treatment rescues neonatal brain injury. Nature 506:230-4
Schneeberger, Marc; Dietrich, Marcelo O; Sebasti√°n, David et al. (2013) Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155:172-87
Matarese, Giuseppe; La Cava, Antonio; Horvath, Tamas L (2012) In vivo veritas, in vitro artificia. Trends Mol Med 18:439-42
Horvath, Tamas L; Abizaid, Alfonso; Dietrich, Marcelo O et al. (2012) Ghrelin-immunopositive hypothalamic neurons tie the circadian clock and visual system to the lateral hypothalamic arousal center. Mol Metab 1:79-85
Ren, Hongxia; Orozco, Ian J; Su, Ya et al. (2012) FoxO1 target Gpr17 activates AgRP neurons to regulate food intake. Cell 149:1314-26
Simon-Areces, Julia; Dietrich, Marcelo O; Hermes, Gretchen et al. (2012) UCP2 induced by natural birth regulates neuronal differentiation of the hippocampus and related adult behavior. PLoS One 7:e42911
Jablonska, Beata; Scafidi, Joseph; Aguirre, Adan et al. (2012) Oligodendrocyte regeneration after neonatal hypoxia requires FoxO1-mediated p27Kip1 expression. J Neurosci 32:14775-93
Klöckener, Tim; Hess, Simon; Belgardt, Bengt F et al. (2011) High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nat Neurosci 14:911-8
Schulze, Christin; McGowan, Margit; Jordt, Sven-Eric et al. (2011) Prolonged oxaliplatin exposure alters intracellular calcium signaling: a new mechanism to explain oxaliplatin-associated peripheral neuropathy. Clin Colorectal Cancer 10:126-33

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