Cellular, molecular, and biochemical principles of aging and age-related disease

We aim to understand aging and age-related diseases from the cellular, molecular, and biochemical levels. Cellular quality control systems respond to and resolve different types of cell stress and are important in maintaining our cellular homeostasis and overall health. However, these quality control systems or stress response pathways are often compromised in aging, causing various diseases. We ask whether we can solve the problem of aging by boosting cellular quality control systems. To answer this question, we are currently searching for all unknown cellular stress response mechanisms through unbiased approaches. Our goal is to combinatorically target multiple stress response pathways to maximize our resistance to cellular stress for healthy aging and for potential treatment of age-related diseases. Our recent discoveries include an essential rapid lysosomal repair pathway (the PITT pathway) in response to lysosomal damage and a conserved ion channel function of stimulator of interferon genes (STING) in non-canonical autophagy which is activated in many conditions including infection, cellular damage, senescence, or age-related diseases such as Parkinson’s and Alzheimer’s diseases. Within the next five years, we will focus on the mechanistic investigation of two processes: (1) lysosomal quality control in response to diverse cellular stress stimuli, and (2) STING-mediated non-canonical autophagy and cell death. We search for essential, unifying principles behind complex stress responses, and dissect the underlying mechanisms using multidisciplinary methods including molecular biology, biochemistry, cell biology, and genetics. Unbiased screens, molecular cloning, cell engineering, and microscopic imaging are among the major strengths of our lab. Structural analysis and functional mutagenesis are integral parts of all our projects. Lipid signaling and membrane biology are also incorporated into all directions.

Education

• S. in Science with Honors from Nanjing University (China), 2005-2009
• D. in Molecular and cellular Pharmacology from University of Wisconsin-Madison, 2009-2015
• Postdoctoral training at the University of Texas Southwestern Medical Center in the laboratory of Zhijian James Chen, 2016-2019
• Research faculty training at the University of Pittsburgh in the laboratory of Toren Finkel, 2019-2022

Aging Institute
100 Technology Drive, Room 457
Pittsburgh, PA 15219
Phone: 412-624-2291
Email: Jay.Tan@Pitt.edu
Phone:4122683390

Website link: jaytanlab.org

Membrane Protein Quality Control, Mitochondria, Cancer, and Neurodegenerative Diseases

Mitochondria are endosymbiotic organelles that serve as key hubs for apoptotic regulation, metabolism, and cellular signaling in eukaryotic cells. Over 99% of the ~1500 mitochondrial proteins are encoded in the nuclear genome and depend on specific targeting signals to direct them from the site of synthesis in the cytosol to the appropriate subcompartment. Proper mitochondrial function depends on a process called proteostasis, which ensures that functional proteins are in the right location at the right concentration at the right time. Membrane proteins present unique challenges to the proteostasis network as they must be targeted to the correct membrane and overcome substantial thermodynamic barriers to enter and exit the lipid bilayer, all while avoiding the formation of potentially toxic aggregates in the cytosol. Failures in proteostasis are associated with many neurodegenerative diseases, whereas cancer cells are acutely dependent on robust proteostasis networks to counteract the protein imbalances caused by aneuploidy and dysregulated protein synthesis.

Despite the clear physiological importance, our mechanistic understanding of mitochondrial proteostasis is remarkably incomplete. My lab addresses this critical knowledge gap by focusing on three questions: (1) How do quality control factors discriminate between bona fide substrates and functional proteins in a complex cellular environment, such as the lipid bilayer; (2) once a substrate is recognized, what are the downstream steps that lead to resolution of proteotoxic stress; and (3) how can we leverage the resulting mechanistic insights to develop therapeutic interventions in cancer and neurodegenerative disease? We address these questions using a combination of biochemistry, biophysics, and structural, molecular, and cell biology.

Education

• Education: Ph.D. 2013, MIT
  
  

Postdoctoral Training

• Postdoctoral Training: 2018, University of Chicago

Mail to:

Lab location:
Department of Cell Biology
3500 Terrace Street
S326 Biomedical Science Tower
Pittsburgh, PA 15261

Office: 412-648-7482
Lab: 412-648-9713

Email: Wohlever@pitt.edu

Website link: https://wohleverlab.wordpress.com/

Structures, mechanisms, and biological roles of new classes of microbial enzymes and microbial natural products

Even in the best-studied microbes, a significant proportion of the proteins and pathways remain unidentified and unstudied. Research in the Kenney Lab focuses on the elucidation of this unexplored microbial chemistry, particularly the structures and mechanisms of new classes of enzymes and natural products. One major area of interest is the identification of new types of metalloenzymes that are involved in the production of secondary metabolites.  A second area of interest is the biosynthesis of peptidic natural products.  A final area of interest involves the identification of natural products with roles in microbial metal homeostasis in complex environments.

Our research is interdisciplinary and draws on a wide range of techniques.  We use bioinformatics and other computational approaches to identify and prioritize interesting biochemical systems, and to model enzyme structure and reactivity.  Natural products are identified and characterized using mass spectrometry and NMR; when investigating enzyme mechanism, this is supplemented by various spectroscopic techniques, the use of substrate analogs, and other structural, biophysical, and bioinorganic techniques as needed. In vivoexploration of these microbial systems can include ‘omics, genetic manipulation of microbes, and other methods for analyzing changes in phenotype and metabolism on the cellular level.   

Education

• S.B.: 2007, Chemistry, MIT
  Ph.D.: 2017, Biological Sciences, Northwestern University (in the laboratory of Dr. Amy C. Rosenzweig)
  Postdoctoral Training: 2023, Harvard University (in the laboratory of Dr. Emily P. Balskus)

Department of Chemistry
219 Parkman Ave.
6^th floor, Chevron Science Center Annex
Pittsburgh, PA 15260
Office phone: 412-383-2264
Lab phone: (not yet available)
Email: gkenney@pitt.edu

Website link: https://www.kenneylab.org/

Our research is focused on elucidating the structure function relationship of cytochrome P450 enzymes in lung cancer using biochemistry, cell biology, and X-ray protein crystallography.

Members of the cytochrome P450 CYP4F family belong to a group of w-hydroxylases which produce important lipid mediators in the human body. One of these lipid mediators is the molecule 20-hydroxyeicosatetraenoic acid (20-HETE) which is regulating the blood pressure and promotes the formation of new blood vessels in healthy humans. In cancer, 20-HETE promotes cell proliferation and invasion and thus, 20-HETE generating cytochrome P450 enzymes might be exciting new drug targets for cancer treatment.

We use a combination of cell biology and biochemistry to assess the role and function of CYP4F enzymes in oncogenesis and cancer progression. Moreover, we use X-ray protein crystallography to solve structures of CYP4F enzymes for directed design of selective drugs which only inhibit the target and not any of the other 56 P450s in the human body.

Education

• Diploma in Molecular and Human Biology from Saarland University (Germany), 2012
• PhD in Biochemistry from Saarland University in the laboratory of Rita Bernhardt (Germany), 2012-2016

Postdoctoral Training

• Postdoctoral training at Saarland University (Germany) in the laboratory of Rita Bernhardt, 2016-2017
• Postdoctoral training at the University of Michigan in the laboratory of Emily Scott, 2017-2021

Mail to:

Lab location:
School of Pharmacy Department of Pharmaceutical Sciences
Center for Pharmacogenetics
Salk Pavilion 3^rd floor, room 305
335 Sutherland Dr
Pittsburgh, PA, 15261

Email: sib51@pitt.edu

Website link: https://brixiuslab.org/