Shamloo Lab Research
The ultimate goal of the Shamloo laboratory and research is to rapidly advance our understanding of normal brain function at the molecular, cellular, circuit, behavioral and functional levels, and to elucidate the pathological process underlying malfunction of the nervous system following injury and neurologic disorders such as stroke, Alzheimer’s disease and autism. I aim to probe and understand the process leading to the functional and behavioral malfunction in these disorders focusing on a set of target genes/proteins which we have discovered to be regulated in the brain in the context of these disorders. My laboratory will use automated behavioral and functional methods and endpoints in the experimental and transgenic rodent models in conjunction with experimental therapeutic approaches such as small molecule therapeutics and stem cell delivery methods in order to manipulate the loss of function in these models. We will focus on neuroprotective and neurodegenerative pathways, aiming to accelerate the translation of these experimental discoveries into novel therapeutic approaches with the fundamental goal of improving the quality of life for patients with brain disorders. Furthermore, we will focus our effort on our translational work with Beta 1- adrenergic ligands as memory enhancers for cognitive disorders. This is a line of research we find very promising and in which we have a pending patent for a small molecule stimulating this receptor. We have now two published manuscripts in this area.
My laboratory is studying the Npas4 (neuronal Per–Arnt–Sim (PAS) domain protein). We have previously characterized Npas4 in the rat brain following ischemic injury and demonstrated that this transcription factor is specifically expressed in the brain and its expression is up-regulated in ischemic tissue following brain injury with particularly strong expression in the limbic system, thalamus, and cortex. My lab has also shown Npas4 null mice display larger brain infarction compared to the control mice indicating a neuroprotective function for this protein. In addition, this mouse line displays substantial learning and memory deficit as well as social function deficit. Npas4 is activated by excitatory synaptic activity, regulating the formation and maintenance of inhibitory synapses on excitatory neurons. Using the NPAS4 null mice, we have shown that NPAS4 is a key molecule in memory formation and social behavior. We will be studying the role of Npas4 and its inhibitory function as a key player following injury, stress, and autism as well as learning and memory.
Study the Beta 1 adrenergic receptor and its regulation as a key pathway in the context of learning and memory as well as pathophysiology of the neurocognitive disorders. The Beta 1 adrenergic signaling cascade will also be evaluated in the context of the social discrimination and social memory in CNS disorders.
A. A working model showing the β1-Adernergic receptors and its disease modifying effects in neurocognitive disorders. B. Chronic or acute treatment with a partial agonist of β1-Adernergic receptor, Xamoterol, induces microglia activation and restoration of Spontaneous Alternation in a mice model of Alzheimer's disease.
Study Npas4 as a key transcription factor involved in processing of the social and cognitive function. Study the importance of NPAS4 in context of the CNS disorders.
Existing protocols in the Shamloo laboratory for staining A) neuronal and B+C) mixed cell culture preparations with actin/MAP2 for neuronal morphology and synaptophysin and PSD95 for synaptic formation will allow for the quantitative and qualitative analysis of effects of cathepsin S and VBY 50365 on these measures.