Driscoll Lab Research Interests

Our lab uses the elegant and powerful model system C. elegans to decipher conserved molecular mechanisms of cellular function and dysfunction.  The main problems we investigate are neuronal degeneration, neuronal regeneration, and the biology of aging, with a focused goal of defining strategies for extending healthspan.

Molecular Mechanisms of Necrotic Neuronal Death

Various cellular insults, including hyper-activation of ion channels, can induce a necrotic-like cell death in C. elegans. Interestingly, injured cells in vertebrates undergo necrotic cell death that shares features of C. elegans necrosis, suggesting a common set of biochemical steps involved in injury-associated cell death as occurs in oxygen deprivation, disruption of membrane integrity, and dis-regulation of calcium homeostasis.  Elucidation of the molecular bases of necrotic-like cell death in simple animal models should provide insight into the basic biology of inappropriate neuronal death and facilitate the characterization of mechanisms underlying degeneration in human disorders.  Our hope is that ultimately molecular genetic dissection of necrotic cell death mechanisms in C. elegans may inspire design of therapies that combat disease- and injury-associated necrosis in humans.

We are genetically and molecularly deciphering C. elegans necrotic death mechanisms, which we can do in a physiological context.  Toward this end, we have identified several novel genes that are required for necrotic-like cell death.  We have also identified genes that can function to protect against necrotic insult.  Our molecular analysis of these genes has defined a pathway for neuronal necrosis involving hyper-activation of plasma membrane calcium channels, induction of ER calcium release, and activation of calpains and other proteases.  We continue to identify novel genes and pharmacological interventions impacting necrosis. Since most C. elegans genes have counterparts in higher organisms, our results should provide new insights into neuronal injury and neurodegenerative disease. 

Aging and the Genetics of Healthspan: Defining Molecular Strategies for Healthy Aging
Design of effective therapeutic interventions that counter deleterious components of aging will require a thorough definition of what actually occurs during aging at the molecular, cellular, and systems levels.  Our lab has become interested in what actually occurs at the tissue and cellular levels as animals grow old.  Our longterm goal is to use our understanding of aging processes to define genes that extend/limit healthspan—the period of healthy maintenance prior to debilitating age-associated decline. 

We have found that cell death per se has little impact on age-related decline but that rather tissue-specific deterioration appears to be a conserved feature of aging.  Somewhat unexpectedly, we note a striking heterogeneity in age-related decline among animals of the same genotype reared under the same experimental conditions, supporting that stochastic influences play significant roles in age-related decline.  Our work has identified potential aging biomarkers that can be used to evaluate physiological rather than chronological age (for example quantitation of age pigments—lipofuscin and advanced glycation end products—can suggest healthy aging and dietary restriction metabolism).  We are currently exploiting these markers to dissect the genetics of healthspan. We have ongoing projects on preventative strategies that combat sarcopenia (the conserved loss of muscle mass and strength that transpires with age), on age-associated dendritic restructuring within neuronal processes, on the role of the EGF pathway in promoting strong maintenance late into life, on the roles of miRNAs in robust, healthy aging, and on the influence of metabolism and metabolism-modifying drugs like metformin in promoting healthspan.  Our overall goal is to define factors that improve the quality of aging and to identify conserved processes that might be manipulated to extend human healthspan.

Neuronal Regeneration at the Single Neuron Level
In addition to our interests in nervous system maintenance, we are also interested in the problem of how to repair severed or diseased neurons. We are addressing the basic molecular biology of regeneration by laser severing individual axons in vivo and directly studying how neurons regrow in the transparent, genetically manipulable, living C. elegans (ongoing collaboration with Dr. Christopher Gabel).  Unexpectedly we have found that apoptosis killer caspase CED-3 acts early within the injured neuron to promote efficient regeneration of laser-severed neurons; this activity appears dependent upon rapid calcium changes in the injured neuron and acts upstream of the role of conserved regeneration kinase DLK-1.  Because a critical accomplishment in the rapidly developing field of regenerative medicine will be the ability to foster repair of neurons severed by injury, disease, or microsurgery, we are exploiting the unique features of C. elegans to dissect molecular strategies for regeneration initiation.