Michael S. Marks, PhD
Professor of Pathology and Laboratory Medicine
Professor of Physiology
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816G Abramson Research Center
3615 Civic Center Blvd.
Philadelphia, PA 19104
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Michael S. Marks, PhD
Professor Of Physiology
Degrees & Education
BS, (Biological Sciences) Cornell University, 1982
PhD, (Immunology/Microbiology) Duke University Durham, NC, 1989
Regulation and diseases of intracellular protein transport and organelle biogenesis
Regulation of the formation of functional amyloid in organelle biogenesis
Regulation of antigen processing and toll-like receptor signaling by endosomal trafficking pathways
Adriana Mantegazza - Senior Scientist
Megan Dennis - Post-doctoral researcher
Ariel Lefkovith – BGS Graduate Student (CAMB)
Tina Ho – BGS Graduate Student (CAMB)
Dawn Harper - Research Associate
Amanda Acosta - Undergraduate researcher
Alexis Borden - Undergraduate researcher
The central vacuolar system of eukaryotic cells is compartmentalized into distinct membrane-bound organelles and vesicular structures, each with its own characteristic function and set of protein constituents. Work in my laboratory is focused on understanding how integral membrane protein complexes are assembled and sorted to the appropriate compartments within the late secretory and endocytic pathways, and how sorting and assembly contribute to the biogenesis of specific organelles in several cell types and to immune regulation.
Our primary focus over the past 10 years has been on melanosomes of pigmented cells. Melanosomes are unique lysosome-related organelles present only in cells that make melanin, the major synthesized pigment in mammals. Melanosomes are among a number of tissue-specific lysosome-related organelles that are malformed and dysfunctional in a group of rare heritable disorders, including Hermansky-Pudlak and Chediak-Higashi syndromes, and pigment cell-specific proteins that localize to melanosomes are targets for the immune system in patients with melanoma. In an effort to understand the molecular basis of these diseases, we are dissecting the molecular mechanisms that regulate how different stage melanosomes are formed and integrated with the endosomal pathway. We use biochemical, morphological, and genetic approaches to follow the fates of melanosome-specific and ubiquitous endosomal and lysosomal proteins within pigment cells from normal individuals or mice and disease models. Using these approaches, we are (1) outlining protein transport pathways that lead to the formation of these unusual organelles, (2) dissecting biochemical pathways that lead to their morphogenesis, and (3) defining how these processes are subverted by genetic disease. Current efforts focus on how factors that are deficient in patients and mouse models of the genetic disease, Hermansky-Pudlak syndrome, impact melanosome biogenesis. These factors interact with classical components of the membrane trafficking machinery such as SNAREs and coats, and we are dissecting how these interactions result in the delivery of cargoes to unique organelle structures in these cells. We are particularly interested in the formation of tubular connections between endosomes and maturing melanosomes, as several factors that are disrupted in Hermansky-Pudlak syndrome impact the formation and/or dynamics of these transport carriers.
Because genetic diseases like Hermansky-Pudlak syndrome affect multiple organ systems, we have initiated two new projects to dissect how similar sorting processes involved in melanosome biogenesis influence other organelles in different cell types. The first involves lysosome-related organelles in platelets called dense granules and alpha granules. Dense granules are organelles within platelets that store small molecules such as adenine nucleotides, polyphosphate, serotonin and calcium that are released upon platelet activation and are required for optimal blood clotting. Like melanosomes, dense granules are malformed in Hermansky-Pudlak syndrome, and we are studying how dense granule contents are delivered within platelets and their precursors (megakaryocytes). In collaboration with Mitch Weiss and Morty Poncz at CHOP, we are studying how cargoes of dense granules are delivered to those organelles in megakaryocytes, and how these processes are altered in Hermansky-Pudlak syndrome and other bleeding disorders. Alpha granules are other lysosome-related organelles in platelets that store secretory protein contents. In collaboration with Morty Poncz and Gerd Blobel, we are studying how alpha granule secretion is altered in a mouse model of a human bleeding disorder.
The second cellular system is the dendritic cell, a master regulator of T cell immune function. Dendritic cells have been proposed to harbor a lysosome-related organelle involved in preventing maturation of phagosomes to facilitate the processing of phagocytosed antigens to stimulate CD8+ (prdominantly cytotoxic) T cells. Paradoxically, we have found that dendritic cells from one Hermansky-Pudlak syndrome model are impaired in their ability to process phagocytosed antigen for presentation to a different class of T cells, the CD4+ (predominantly T helper) T cells. Preliminary studies suggest that the antigen processing defect results from a primary defect in toll-like receptor signalling from phagosomes, and current projects are devoted to better understanding this defect at the molecular level.
Melanosome precursors harbor intralumenal fibrils upon which melanins deposit in later stages. The main component of these fibrils is a pigment cell-specific protein, Pmel17. Fibrils formed by Pmel17 in vitro display features common with amyloid formed in disease states such as Alzheimer's disease and the prion diseases. We hope that by dissecting how Pmel17 forms amyloid like fibrils under physiological conditions, we may not only understand melanosome biogenesis but also the formation of amyloid under pathological conditions.
Click here for a full list of publications.
(searches the National Library of Medicine's PubMed database.)