2014 — 2018 |
Rajan, Akhila |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Systemic Regulation of Energy Homeostasis Using a Drosophila Leptin Model
DESCRIPTION (provided by applicant): Coordination of food intake and utilization of nutrient stores is referred to as energy homeostasis. When this fundamental process is disrupted, it can lead to a number of disorders, in particular, obesity, anorexia and diabetes. I found that a ligand of the JAK/STAT pathway in flies, called Unpaired2 (Upd2), functions like Leptin in fruit flies. It signals the organism's fat status to GABAergic neurons in the brain. Current working model suggests that JAK/STAT signaling promotes insulin secretion by relieving the inhibitory tone of GABA neurons on insulin producing cells (IPCs). This circuit module is strikingly reminiscent to that used by Leptin to control energy balance in the mammalian system. In this proposal, using the Drosophila system Leptin model, I propose to investigate the following: i) how fat levels regulate Upd2 at the level of secretion; ii) identify mechanism(s) by which Leptin and Upd2 signaling affects GABAergic neuronal firing are unknown. I will test whether the role for STAT in GABAergic neurons is transcriptional or post- transcriptional. Then, I will identify STAT's targets and/or its protein interactors which are involved in Upd2- mediated regulation of GABA neurons; iii) finally, using an innovative technique, I plan to identify neurons which respond to particular sorts of diets and determine the molecular profile of such neuronal groups. This is expected to provide information about the cellular identify of the neuronal group which responds to dietary changes. This will guide subsequent studies of how a particular set of neurons influence systemic energy metabolism in response to specific diets. Overall, the proposed aims will address two key issues in Leptin Biology: i) how adipostatic molecules are regulated at the level of translation and secretion in response to changes in nutrient stores; ii) what molecular mechanisms are deployed by these molecules to alter neuronal physiology in response to dietary changes. The 2010 policy document-Dietary guidelines for Americans- issued by the USDA finds that, an increased intake of fats, sugars and refined grains in lieu of protein-rich food, is a primary cause of chronic diseases such as cardiovascular disorders, diabetes and some forms cancer. In order to negate the effects of high fat and sugar diets, elucidating the molecular basis of systemic fat metabolism is crucial. The studies I propose here have the potential to illuminate why we prefer fat-rich foods to a protein-rich diet and importantl will provide relevant insights for the treatment of complex metabolic disorders.
|
1 |
2017 — 2021 |
Rajan, Akhila |
R35Activity Code Description: To provide long term support to an experienced investigator with an outstanding record of research productivity. This support is intended to encourage investigators to embark on long-term projects of unusual potential. |
Investigating How Cellular Mechanisms Interface to Maintain Energy Balance @ Fred Hutchinson Cancer Research Center
Project Summary: Organisms, from bacteria to humans, modulate their food intake and energy expenditure in accordance with their internal nutrient state, allowing for maintenance of healthy energy balance. During evolution conserved homeostatic mechanisms developed to cope with potential nutrient deprivation from a fluctuating food supply. Hence when food was plentiful the excess energy is stored as fat reserves, which can be mobilized during a future scarcity. However, in the 21st century nutritional scarcity is the exception rather than the norm, resulting in an increasing prevalence of obesity in humans. Obesity impacts progression of cancer and neurodegeneration, accelerates aging and impedes a healthy lifestyle. Previously, a number of studies focused on how organisms respond to nutritional scarcity, and have resulted in elucidation of evolutionarily conserved mechanisms that orchestrate a response to food scarcity. Our aim is to understand the opposite nutritional state, by focusing on how organisms respond to chronic ?over-nutrition?. We expect that these mechanisms will be both short-range, acute, local cell biological changes and also prolonged time-scale, inter- organ systemic physiological responses. Thus far, we identified previously uncharacterized surplus signaling components. Unexpectedly we found molecules that are critical for scarcity responses, are also key regulators of nutritional surplus. Given that storage of surplus evolved as a protective strategy to survive future nutritional scarcity, it is likely that an overlapping set of molecules is employed to allow organisms to sense and respond to these two mutually exclusive states. Premised on our observations, we hypothesize that a suite of ?bidirectional? switch proteins couple scarcity and surplus mechanisms, allowing organisms to toggle between the two as needed. We further surmise that chronic nutrient surplus, a state that was rare during the evolution, impairs the capacity of this ?bidirectional molecular switch? to efficiently alternate in response to nutritional state, resulting in energy imbalance. Our short-term goal is to a) codify the molecular suite underpinning the bidirectional nutritional switch; b) identify new bidirectional nutrient switches that facilitate inter-organ communication required for energy balance. Then, in the medium-term we will c) systematically dissect how the bidirectional mechanisms degrade and lose plasticity when subject to chronic nutrient surplus. Finally, our long-term goal is to d) develop pharmaceutical interventions that target the bidirectional molecular suite, and test their effect in restoring energy balance in systems that have been nutritionally stressed. The fundamental principles we derive from this work will illuminate how molecular components designed to function in a certain physiological state can be co-opted to achieve an antagonistic response. The principles garnered from our studies will be applicable to understanding how viruses hijack immune cells, or explain how cancerous cells trick cell-death pathways and over-proliferate. Ultimately our goal is to address outstanding issues in energy physiology, by adopting a comprehensive and conceptually novel approach, in a highly tractable model.
|
1 |