Kaveh Ashrafi, PhD

Professor
Department of Physiology
+1 415 514-4102

The overall goal of our lab’s research project is to understand energy balance in the context of intact animals, how metabolism affects neural functions, and how aberrations in energy balance underlie pathological conditions such as type 2 diabetes, cardiovascular disease, hypertension and cancer.   Most of our work relies on experimental advantages of C. elegans although we conduct some mouse studies through collaborative efforts.  Our approaches involve a combination of molecular genetics, imaging, biochemistry, and chemical biology.  The current areas of research can broadly be defined as below:

  1. Analyses of neural fat and feeding regulatory circuitsA number of neurally active signaling pathways, such as serotonin signaling, centrally coordinate fat and feeding pathways in C. elegans.  Using functional genetic studies we are delineating the neural and molecular circuits that link perception of nutrient availability to various behavioral, physiological and metabolic outcomes. 

  2. Metabolic regulation of neural functions and behavioral plasticity.  C. elegans exhibit food-modulated behavioral plasticity.  For instance, following fasting, C. elegans temporary over-eat once they have been re-exposed to food.  We recently discovered that neural production and depletion of a specific metabolite of the tryptophan degradation pathway, known as kynurenic acid, serves as mechanism through which the experience of fasting becomes manifested in differential neural activities and subsequent behavioral outcomes.  We are now investigating the role of this pathway in underlying the beneficial effects of caloric restriction on enhanced learning and memory.  This pathway has already been linked to human neurodegenerative and psychiatric disorders thus our findings are likely shedding light on an ancient mechanism that couples metabolism to brain functions.

  3. Analysis of C. elegans counterparts of human obesity genes.  We are analyzing key metabolic fuel gauge pathways such as the TOR kinase and AMP-activated kinase, which bridge cellular metabolic pathways to growth and differential pathways.  Additionally, we are investigating C. elegans counterparts of human obesity genes.  For instance, we recently demonstrated that, in C. elegans as humans, mutations in Bardet-Biedl syndrome (bbs) genes, cause fat accumulation.  As the complex of BBS proteins is required for proper formation and functioning of cilia, cellular organelles enriched in signaling molecules, it is widely assumed that obesity of bbs mutants must be due to inappropriate localization of receptors with roles in body weight regulation.  By analyzing the C. elegans bbs mutants, we discovered that while these mutants indeed have ciliary defects, the excess fat of these animals derives from excess secretion of dense-core vesicles rather than inappropriate signal receptor by cilia-localized receptors.

  4. The role of environmentally pervasive pollutants in the rise of obesity.  Just as certain chemicals pervasive in our environment act endocrine disruptors with adverse effects on reproduction or development, epidemiological studies and animal experiments already show a link between exposure to environmental chemicals and obesity. The idea of environmental ‘obesogens’ is not novel, but a formidable challenge has been identifying the molecular mechanisms of putative obesogens. The experimental challenges in this area are further complicated by the fact that obesogenic consequences of these compounds may be due to low dose combinatorial effects or due to epigenetic programs. This lack of molecular clarity has marginalized consideration of these agents as key drivers of obesity. To address this issue, we are using C. elegans both to screen for environmentally pervasive compounds that can act as fat increasing drugs and use worms to decipher their mechanisms of action.   

  5. Identification and analyses of molecular mechanisms of action of fat altering drugs.  We have leveraged the experimental advantage of C. elegans to screen through compound libraries of Small Molecule Discovery Center at QB3 to identify those that alter C. elegansfat.  In collaborative efforts with laboratories of Dr. Shoichet (UCSF, QB3) and Dr. Roth (UNC-Chapel Hill), we have begun efforts aimed at understanding the mechanisms of actions of these compounds in the context of whole animals by combining in silicopredictions with in vitro and in vivo validation of these predictions on C. elegans and mammalian pathways.

Primary Thematic Area: 
Tissue / Organ Biology & Endocrinology
Secondary Thematic Area: 
Neurobiology
Research Summary: 
at, Feeding, and Metabolic Regulation of Neural Functions

Websites

Publications: 

Investigating Connections between Metabolism, Longevity, and Behavior in Caenorhabditis elegans.

Trends in endocrinology and metabolism: TEM

Lemieux GA, Ashrafi K

Conserved Genetic Interactions between Ciliopathy Complexes Cooperatively Support Ciliogenesis and Ciliary Signaling.

PLoS genetics

Yee LE, Garcia-Gonzalo FR, Bowie RV, Li C, Kennedy JK, Ashrafi K, Blacque OE, Leroux MR, Reiter JF

Neural Regulatory Pathways of Feeding and Fat in Caenorhabditis elegans.

Annual review of genetics

Lemieux GA, Ashrafi K

Kynurenic acid is a nutritional cue that enables behavioral plasticity.

Cell

Lemieux GA, Cunningham KA, Lin L, Mayer F, Werb Z, Ashrafi K

Insights and challenges in using C. elegans for investigation of fat metabolism.

Critical reviews in biochemistry and molecular biology

Lemieux GA, Ashrafi K