Jeffrey
Henderson

Drug Development and Disease Diagnostics
Molecular basis of drug targets and diseases

144 College Street
Toronto ON M5S 3M2
Canada

Area of Research

Jeff Henderson’s research focuses on the molecular mechanisms regulating programmed cell death (PCD) in the mammalian central nervous system (CNS) in both normal and pathologic states, neural connectivity in the CNS as relates to Eph-family tyrosine kinases, and the development and delivery of small molecule therapeutics targeting these processes.

Research Challenge

Following many forms of CNS injury, damaged cells are eliminated through a process known as programmed cell death (PCD). PCD regulates a number of normal cellular process (tissue morphology, immune function, etc.), both during development and in response to a variety of environmental stressors and cell pathogens. PCD (apoptosis, necroptosis, cellular autophagy) also regulates cell death in acute injury states such as spinal cord injury and stroke, and in neurodegenerative diseases including Alzheimer’s, Parkinson’s and Huntington’s. It is also abnormally regulated in a wide array of human cancers. Therefore, understanding PCD is critical to modifying these processes.

In addition to cell death, repair of the injured CNS requires proper re-growth/innervation of neurons. Given their large number, guidance molecules direct proper reconnection. Eph receptors are the largest family of such neural/axon guidance molecules. Understanding how these molecules work allows us to promote proper reconnection of the CNS following injury.

Proposed Solution

Regulating the inhibition or enhancement of various forms of cell death is currently an area of intense pharmaceutic and clinical interest in the treatment of neurodegenerative disorders and cancer therapy, respectively. A key problem has been identifying those critical molecular interactors that regulate core cell death machinery. To identify these (and determine potentially redundant signaling mechanisms), the Henderson laboratory is examining the role of PCD interactors, both individually and in conjunction with other family members in each of the cell death pathways, using a targeted gene modification (Crispr) approach in primary (ES/iPS) stem cells. The laboratory uses this integrated network approach to functionally identify the response patterns of a series of primary cells in vitro and in vivo to an array of cellular stressors, allowing the rapid identification of likely small molecule therapeutics. To enhance CNS delivery of such therapeutics, the laboratory collaborates with Dr. S. Wu to develop nanoparticle agents.

Impact to date

The laboratory published high-throughput screen of more than 6000 GRAS compounds, identifying small molecule modifiers of PCD. Modulation of PCD is currently considered to be a leading avenue of development of practical inhibitors of cancer cell growth. They also published first CNS surgical atlases of C57bl6J, 129SV/img and CD1, widely utilized in experimental studies of human disease, and they developed an improved rodent model of cerebral ischemia, identifying causes of recent clinical drug failures.

The Henderson laboratory has made pioneering discoveries in their field. The laboratory first identified role of Bcl-2 in regulating gamma motor survival in vivo; first demonstrated in vivo role of Smac/DIABLO in controlling programmed cell death; published the first description of neuronal effects Traf-6; published first demonstration of the role of EphB family receptors in vivo (with the laboratory of T. Pawson); first demonstrated in vivo role of intracellular adaptors ShcB and ShcC play in regulating CNS development; and published the first description of caspase-9 null mice, a central regulator of PCD (in conjunction with R. Hakem).

Publications

Henderson laboratory publications


Keywords: mouse model, CNS, embryonic stem cells, cell death, CRISPR, transgenics, small molecules, programmed cell death, stroke, neural connectivity,  axon guidance, gene transduction methods, stereotactic, microsurgical methods, neuroanatomy