Thomas J. Melia, PhD.

Assistant Professor of Cell Biology
Phone: (203) 785-2165 Lab: (203) 737-4048 Fax: (203) 785-7446 e-mail: thomas.melia@yale.edu		Department of Cell Biology Yale University School of Medicine 333 Cedar Street PO Box 208002 New Haven, CT 06520-8002 <Courier Address> 295 Congress Ave, BCMM 254C (Lab BCMM 249) New Haven, CT 06519-1418

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Education

B.S. Carnegie Mellon University, 1992

Ph.D. Baylor College of Medicine, 1999

Background

Macroautophagy (herein referred to as autophagy) is classically defined as a pathway for the nonspecific sequestration and degradation of cytosolic material when the cell is faced with persistent starvation.  This cytosolic material is captured within a double-membraned vesicle (the autophagosome) which forms de novo and ultimately traffics the material to the lysosome for degradation (and release of valuable nutrients). However, this pathway can also be utilized as a stress response to a wide variety of cellular insults and as such its involvement in disease seems nearly ubiquitous. 

Significant effort has been invested on elucidating and manipulating regulatory signals which initiate (or block) autophagosome biogenesis.  These efforts show real promise when autophagic activity is limiting, i.e. where the base-line response to sudden or chronic stressors is insufficient or during extended exposure to nutrient-poor environments. 

Unfortunately, a large number of autophagy-related disease states are consistent with changes within the autophagic cycle rather than with the overall steady-state level of autophagy, such that autophagic intermediates accumulate or autophagosomal membranes fail to sufficiently engage potential autophagic substrates.  For example, autophagic clearance of protein aggregates, a process correlated with amelioration of certain neurodegenerative disease symptoms is slow by an order of several magnitude when compared to the normal ~10 minute autophagic turnover of cytosol.  Perhaps similar is the accumulation and persistence of autophagosomes in lysosomal storage disorders where the natural processes of lipid degradation are blocked. In general, failure to properly capture, sequester, or process toxic substrates through autophagic activity is thought to underlie diseases ranging from Alzheimer’s to tumorigenesis. 

Questions

Why do certain toxic challenges slow or abort the autophagic maturation? What machineries identify potential cargo?  These questions are inherently difficult to address because they require a detailed understanding of the underlying membrane architectures and transitions that accompany autophagy.  To date, we know very little about these transitions and have virtually no grasp of the fundamental protein activities that give rise to each of the (putative) autophagic intermediate states. How autophagosomes form, what membranes they derive from, how cargo is recognized, and how these cargoes are enclosed in a double membrane is each poorly understood. Classic genetics approaches have revealed a large number of autophagy-related genes (ATG genes) and disease exploration continues to undercover new stress-related autophagy substrates, but how the ATG proteins target these substrates for degradation remains unknown.  A primary thesis of my lab is that the physiologic consequences and therapeutic potential of autophagy cannot be well understood until fundamental questions of autophagosome biogenesis and maturation have been addressed.

Publications Since 2006

Giraudo, C.G., Eng, W.S., Melia, T.J., and Rothman, J.E. 2006. A clamping mechanism involved in SNARE-dependent exocytosis. Science, 313, 676-680.

Melia, T.J., You, D., Tareste, D.C., and Rothman, J.E. 2006. Lipidic antagonists to SNARE-mediated fusion. J. Biol. Chem., 281, 29597-29605.

Shen, J., Tareste, D.C., Paumet, F., Rothman, J.E., and Melia, T.J. 2007. Selective activation of cognate SNAREpins by Sec1/Munc18 proteins. Cell, 128, 183-195.

Melia, T.J. 2007. Putting the clamps on membrane fusion: how complexin sets the stage for calcium-mediated exocytosis. FEBS Lett., 581, 2131-2139.

Li, F., Pincet, F., Perez, E., Eng, W.S., Melia, T.J., Rothman, J.E., and Tareste, D. 2007. Energetics and dynamics of SNAREpin folding across lipid bilayers. Nat. Struct. Mol. Biol., 14, 890-896.

Tareste, D., Shen, J., Melia, T.J. and Rothman, J.E. . SNAREpin/Munc18 promotes adhesion and fusion of large vesicles to giant membranes. Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2380-5.