[Applause] so let's think about what happens when someone in our household is sick right so first of all we put all of our effort towards the person who's sick right we want to make them better we want to give them support maybe we have to go and get things at the store for them and bring them back home some medicine to help them get better but in addition to that it also kind of disturbs our whole balance that we have right in the household so if it's a child that's sick that means a parent might have to stay home and change their schedule or if it's a parent that's sick then the other parents can have to change their schedule to allow and make up the difference for the person that's sick in the household so the brain and spinal cord are like this so when one of the cells in the brain of spinal cord is infected or injured or is under stress they also are a household and the brain and the spinal cord make up the central nervous system and they function together and they have walls like our house has so our house has walls we don't let people in from the outside and this is the same with the brain and spinal cord they are separated from the rest of the body by the blood brain barrier and this barrier then restricts what can come in and out of the brain and spinal cord because the function that the brain and spinal cord do are absolutely critical right we wouldn't survive without them functioning properly and so this highly regulated system has been developed to protect the brain and spinal cord so the bloodb brain barrier is actually a tight Junction of endothelial cells that regulates and decides who can come in and who can't come in very much like our house we have a door to our house and it decides who we're going to let in who we're going to invite in and who we keep on the outside so who are the members in the CNS household well first and foremost we have the neurons right they are the most important cell they control the functioning the movement our feelings everything in our body is controlled through the neurons so they are the most important and critical cells and so the other cells in the CNS are kind of the support to make sure the neurons can do their functions properly so the largest group of cells are the gleo cells and of those is the oligodendrocytes and these cells have myelin and this myelin goes and it wraps around the neurons and it insulates neurons so that the neurons can send their signals um very evenly because neurons are very very long and so it allows them to send their signals across long distances then there are the asites and the asites are the most abundant cell type they make this really dense Network in which these CNS environment exists and they they secrete factors that again support the neurons in their normal functions and finally we have the microa so microa are the immune cells of the central nervous system so they are often called macras type cells and that is true and that their original origin is myoid but they very very early in development of the CNS is they come from the Yol so this is extremely early in development and they go to the developing brain and spinal cord and they play a critical role in development so they phagocytose tissue and they help form synapses between the neurons so once development is done and you have a developed brain and spinal cord they just stay there as residents and they exist there for the lifetime and they just repopulate themselves within the CNS so microa are these really unique innate immune cells they have um a very unique function in that they can recognize things that are not self so they can recognize pathogens like viruses and bacteria they can also recognize damaged tissue so tissue that's not normal and they recognize this through innate immune receptors that are on their cell surface and when these innate immune receptors recognize that there's something not right they initiate an an immune response by the microa and then the microa will secrete immune factors and mediate the development of the immune response in the central nervous system so what's really interesting and unique is that microa Express every innate immune receptor that has been identified and this is not like other immune sub cell types they will only express certain subsets so micr are finely tuned to respond to anything because they're the only immune cells in the CNS right so they have to protect and be able to detect whatever happens in the CNS and this is what they do they they are they are constantly moving um they have little projections and they constantly are moving around and checking out the CNS environment they go over the neurons and make sure um there's everything is all right but again if they sense that something is wrong through these innate immune receptors then they respond so imagine a virus infection right so the microgo will sense that there is a virus in that has come and broken through the bloodb brain barrier they recognize the virus through these innate immune receptors and then the microG become activated and they secrete cyto kindes chemokines and eector molecules so the cyto kindes can actually be antimicrobial so they can they can inhibit the virus replication and and and control the pathogen that has entered the cyto kindes also activate the other microa and asites around them to respond letting them know there's an infection we need help then they secrete Chemin that bring cells into the site of infection to initiate this immune response so that they can get rid of the pathogen now if the CNS cannot control it themselves so the microa cannot control this infection then they send out these cyto kindes that will open up that bloodb brain barrier the tight Junction and they send out chemokines and then then they allow cells from the blood to come in and help fight the infection and these peripheral immune cells include your t- cells and your B cells and other macras and then they come in and together the the local inflammatory response by the microa and these infiltrating cells will clear the virus infection right and everybody gets better this is this is great right so the inflammatory response that is initiated by microa when they're activated is called neuroinflammation and in the scenario I just talked about it's good right so you've cleared the virus infection and everybody's healthy the CNS can continue doing its functions as it is supposed to but sometimes this neuro influ stays too long and this is associated with neurological diseases such as multiple sclerosis and chronic pain and um and dementia has also been included in this group as well as other neurological diseases so let's explore this a little bit more so we're talking about multiple sclerosis so that virus infection that we had if the inflammatory response by the microa stays too long or is too strong it can actually release factors that cause damage to other CNS cells namely the alod dendrites so when oligodendrocytes become exposed to these inflammatory markers they will actually lose myelin expression and so now your neurons lose that insulation the myelin wrapped around those neurons doesn't have that insulation anymore and so the signals can't transmit as well and so that's when you start to have neurological problems right you start to have little ticks and things like that so once the neurons are demyelinated though then the neurons can become targets to these factors that are being secreted and then you have damage to the neurons and even loss of neurons and then you have complete loss of a function right so that's where you have neurological fun loss of neurological function and you develop paralysis and so that's what happens and multiple sclerosis so microa play a critical role in this Progressive neuroinflammation that occurs during progression of multiple sclerosis so let's talk about another scenario how about chronic pain so pain is something that's normal so you something around your body you you have an injury or you have a disease and you feel pain so in this diagram I'm showing you there's um a something happens to your foot you have an injury to your foot but let's talk about something more relevant to us in the dental school and we'll talk about temporal mandibular joint disease so people with TMD will have pain and it's mainly in the jaw or the muscles the masser muscles and they have this pain and the reason they have that is that there are nerve endings in the tissue and those will recognize when there's you know injury or disease they will recognize signals and that's how you elicit pain so from the nerve endings then the signal goes to the trigeminal ganglia which is in um for the the facial in the diagram that's shown behind me it's actually showing from the foot it goes to your dorsal root ganglia so it basically goes to the ganglia and you're having this pain response okay so this is all normal now if this pain response gets too strong or too long the neurons from the ganglia actually terminate in the central nervous system when we're talking about TMD and oral facial we're talking about those neurons actually terminate in the trigeminal brain stem and the microa and the neurons remember they are close together okay so these cells are like touching each other and so microglia and neurons have a normal communication right so that in that normal state microgo secrete growth factors and survival factors that help the neurons function so that's normal state but now if those neurons are excited because of the pains that they the signal that they received they become excitatory and then they release factors because they're under stress and these factors can include ATP or neuropeptides and the innate immune receptors that are on the microa recognize these as stress signals danger signals and so they feel like they have to respond so now the microa become activated and they start secreting factors those immune factors and the immune factors can then in turn bind to receptors on the neurons and when they bind those those factors that are being secreted by microa it actually enhances that excitatory state of the neurons and now you have intense pain and Contin ual pain and it makes this feedback loop between the neurons and the microa they keep each other activated right the neurons activate the microa the microa keep neurons activated and now you've created this big feedback loop between the two and this is sometimes referred to as uh centralized pain so when the pain goes into your into your central nervous system and the pain that originated it out in the periphery whether it was your foot or you know TMD that might have subsided whatever that initial injury or insult was that could have subsided but now you've created this Loop that can't be turned off that's between the microa and the neurons so my research focuses on this interaction right so my research focuses on how can we work to control the inflammatory response by microa in these different neurological diseases so what we're trying to figure out is how how do microa become activated how do they stay activated for so long and most importantly how can we turn them off right so we do a lot of work I work with some pharmaceutical chemists where we're developing new compounds that can reduce the inflammatory response by microa um I also use micro rnas and naturally produced proteins um that also can turn off that inflammatory response by microglia so we're talking about multiple sclerosis is we really want to turn down the inflammatory response by microa and we also want to promote an anti-inflammatory response and repair mechanisms within the microglia so that's what we're focusing on when we're working in multiple sclerosis we want to convert those microglia from that inflammatory State into um more of a of a reparative and controlling the general inflammatory response which happens from infiltrating cells now when we're talking about chronic pain what we really want to do is we want to interrupt this pathway that I was just talking about between the neurons and the microa so opioids are very effective in treating pain and they target the neurons but unfortunately there's side effects to those so what we're trying to do is come in from the microa so can we turn off the microa so that they don't contribute to that feedback loop so if if the neurons don't continue to get those activation signals will they eventually calm down and then the pain would subside so that's what we're working on and um and we really spent a lot of time working on the molecular mechanisms by which these pathways are activated so we're looking at receptors um signaling Pathways and trying to identify specifically which proteins and and molecules are involved in that so we can develop more targeted therapies so we want to specifically turn off the bad parts of neuroinflammation but keep the good parts of neur inflammation so neuroinflammation is good as I described it's very important to protect from infection it's very important after injury to help repair the tissue so neuroinflammation is very good and it it was designed again to protect the CNS right protect our house right we want to protect and it works really well in most cases but sometimes it goes a little bad right so you have too much NE inflammation or it lasts too long and then you can fall into those diseases like chronic pain and multiple sclerosis and so just like our household when someone is sick we want to make them better and when they get better we should all return back to normal right where the way we were and that's what we're trying to do here we just want to take the the CNS and return it back to that normal state where it was so that everybody's healthy and everybody's happy