The Karpac Lab is broadly interested in the origins of signaling networks that provide animals with metabolic flexibility, and thus the capacity to balance energy homeostasis. These ancient networks, under intense evolutionary pressure, both respond to and are shaped by diverse inputs, such as nutrient availability, pathogens, and aging. We primarily use the fruit fly Drosophila melanogaster as a genetic model to investigate the function and integration of these signaling networks at multiple levels of biological organization: from molecules, to cells and tissues, to inter-organ communication, to organismal physiology and aging. Through collaborations, we are also exploiting unique features of our Drosophila models, in combination with mouse and human models, to explore disease signaling mechanisms. Below are some examples of the questions we are currently exploring in the lab (as well as our funding sources):
CELLULAR AND SYSTEMIC COORDINATION OF ENERGY HOMEOSTASIS
for example: How do diverse tissues with unique metabolic functions coordinate signaling pathway responses to autonomously and systemically balance energy homeostasis?
How does the spatial organization of metabolic organs (i.e. proximity to other metabolic organs) within a complex body plan influence the balance of energy homeostasis?
How does nutrient availability or diet shape the complexity of metabolic signaling pathway integration (both acutely and evolutionarily)?
Animals must carefully balance energy use with energy demands, primarily through the control of carbohydrate, lipid, and amino acid metabolism, in order to promote complex biological process such as development, growth, and reproduction. This balance is also required to drive metabolic adaption during shifts from food abundance to food scarcity, or in response to more acute changes in dietary composition and feeding behaviors. Furthermore, the evolution of complex organ systems in metazoans has dictated that the maintenance of energy homeostasis requires coordinating local and systemic energy demands between organs with specialized functions. Fruit flies, like many animals, store large amounts of lipids for energy in functionally analogous tissues, using evolutionarly conserved enzymatic and metabolic signaling pathways regulating lipid breakdown, synthesis, and usage. Drosophila is thus emerging as an important model for exploring the complex integration and coordination of lipid metabolism, and corresponding metabolic signaling pathways, throughout the organism. For example: How does a major energy usage tissue, such as the muscle, communicate energy requirements with tissues that primarily synthesize, store, and supply lipids to the rest of the organism, such as adipose tissue?
COORDINATION OF METABOLIC AND INNATE IMMUNE RESPONSES
for example: How and why do innate immune signaling pathways direct cellular metabolism?
How does diet impact innate immunity?
Metabolic and innate immune responses, two primitive systems critical for the long-term homeostasis of multi-cellular organisms, have evolved to promote cooperative, adaptive responses against diverse environmental challenges. More directly, metabolic signaling pathways/transcription factors can shape innate immune responses through the regulation of innate immune gene expression, and innate immune responses (either cell-autonomously or through systemic inflammation) can alter metabolic signaling pathway activity as well as regulate metabolic gene expression.
We are currently using the fruit fly as model system in order to uncover the ancestral mechanisms that underlie the integration of metabolic and innate immune responses. Drosophila provide unique features, such as integrated organ systems, simplistic microbiota composition, and well-characterized bacterial enteropathogens, that can be leveraged to establish an innate immune-metabolic signaling framework. For example, the fly has many integrated organs (such as the fatbody, a tissue most similar to mammalian adipose) that combine various nutrient and pathogen sensing (innate immune) systems in a single tissue, ie. before these systems evolved into more complex organ types in mammals.
THE AGING SYSTEMIC MILIEU
for example: How are diverse signaling mechanisms systemically coordinated between different tissues during aging?
Aging is characterized by a drastic decline in tissue function, and this decline in function can fundamentally alter metabolic and innate immune homeostasis, ultimately affecting an organisms lifespan. Individual tissues can drive the rate of aging of the entire organism by influencing the extra-cellular systemic environment (milieu), suggesting that the systemic coordination of tissue homeostasis is a critical process of normal aging through the regulation of both ‘pro-aging’ and ‘anti-aging’ systemic (blood-borne/endocrine) factors. Genetically accessible model systems such as Drosophila promise to help identify and characterize such signals. In order to uncover systemic mechanisms that coordinate tissue aging, we are developing fly genetic models, coupled with transcriptomics and functional genomics, that will: (i) aid in the identification of novel systemic factors/mechanisms that promote tissue cross-talk during aging, and (ii) allow for high throughput, in vivo genetic screening of these candidate factors and signaling pathways to determine their role in the regulation of tissue aging, metabolic homeostasis, innate immune homeostasis, and longevity.
THE IMPACT OF DIETARY LIPIDS ON NANOSCALE SIGNALING
for example: Utilizing Drosophila as an in vivo model to explore the role of membrane-targeted dietary lipids in cancer signaling and aging
Many types of signaling components originate from transient nanoscale compartmentalized regions of the plasma membrane composed of specific proteins and lipids. The highly specific lipid composition of these nanodomains, termed nanoclusters, facilitates effector recruitment and therefore influences signal transduction. We utilize Drosophila to explore the role of dietary lipids (such as n-3 PUFAs or cholesterol) in shaping nanoscale signaling components (such as receptors or effector proteins) at the plasma membrane in vivo, and thus to inform on the ability of these lipids to impact cancer or age-related diseases mechanisms in murine and humans models (in collaboration with the Chapkin Lab, TAMU - Program in Integrative Nutrition and Complex Diseases). These fly models help demonstrate the unique properties of certain dietary lipids in shaping nanoscale proteolipid complexes and support the emerging role of plasma membrane-targeted therapies in age-related diseases such as cancer.
FUNDING SOURCES
