Regulation of the Serotonin Transporter Function by Integrins in the Mouse Brain

描述（由申请人提供）：合并抑郁障碍的存在增加冠心病患者发病率和死亡率的风险。5-羟色胺能功能障碍被认为会导致情绪障碍，也是心脏病的一个危险因素，这提高了5-羟色胺稳态改变导致神经精神疾病和心血管疾病共病的可能性。最近，我们发现了5-HT转运体（SERT）和整合素之间的物理和功能相互作用。血小板中有3个。而积分呢？3对血小板功能至关重要，SERT在神经元5-HT信号的调节中起着突出的作用。积分素？3多态性Leu33Pro与心血管疾病相关，因为整合素信号和血小板聚集增强。这个吗?由于SERT表面表达和活性的上调，3变异也与自闭症患者的高血清素血症有关。我们的初步研究表明整合素？3在突触前表达(作为二聚体？V？3)，其中它与SERT物理关联。其他研究表明，对？V？3信号直接影响SERT功能。这些发现导致了我的假设，即SERT/ V？3复合体代表了突触SERT调控的一个关键和保守的方面，模仿其在血小板中的作用。这一建议寻求1)阐明V？3 .影响SERT； 2)建立？V？3)了解Leu33Pro ？3 . SERT函数的编码变异。在Aim 1中，我们关注于映射？利用生化和体外方法研究SERT中的3结合域，为开发可以破坏SERT/ ?V？体外3种相互作用。在目标2中，我们使用小分子？V？3个配体来描绘？V？3激活体外SERT功能，以及体内5-HT清除。在目标3中，我们确定了Leu33Pro ？血小板和大脑中5-羟色胺水平和SERT活性的3变异。我们假设整合素Pro33？3会导致血小板和大脑中SERT功能的组成性升高。总之，这些研究代表了第一次有机会检查？V？并有助于阐明支持精神疾病和心血管疾病之间共病的途径。

DESCRIPTION (provided by applicant): The presence of a comorbid depressive disorder increases risk for morbidity and mortality in patients with coronary heart disease. Serotonergic dysfunction is thought to contribute to mood disorders and is also a risk factor for heart disease, raising the possibility that altered 5-HT homeostasis contribute to comorbidity between neuropsychiatric and cardiovascular disorders. Recently, we discovered a physical and functional interaction between 5-HT transporter (SERT) and integrin ?3 in platelets. While integrin ?3 is essential for platelet function, SERT plays a prominent role in the modulation of neuronal 5-HT signaling. The integrin ?3 polymorphism Leu33Pro is associated with cardiovascular disease due to enhanced integrin signaling and platelet aggregation. This ?3 variant is also associated with hyperserotonemia in autistic patients, due to its upregulation of SERT surface expression and activity. Our preliminary studies indicate that integrin ?3 is expressed presynaptically (as the dimer ?V?3), where it physically associates with SERT. Additional studies suggest that manipulation of ?V?3 signaling directly influences SERT function. These findings lead to my hypothesis that the SERT/ ?V?3 complex represents a critical and conserved facet of synaptic SERT regulation, mimicking its actions in platelets. This proposal seeks 1) to elucidate the physical basis by which ?V?3 influences SERT, 2) to establish the contribution of ?V?3-based activation to SERT regulation and 3) to understand the impact of Leu33Pro ?3 coding variation on SERT function. In Aim 1, we focus on mapping the ?3 binding domain in SERT utilizing biochemical and in vitro approaches, providing a route to the development of small peptides that can disrupt SERT/ ?V?3 interactions ex vivo. In Aim 2, we utilize small molecule ?V?3 ligands to delineate the influence of ?V?3 activation on SERT function ex vivo, as well as 5-HT clearance in vivo. In Aim 3, we determine the effects of the Leu33Pro ?3 variant on 5-HT levels and SERT activity in both platelets and in the brain. We hypothesize that the expression of integrin Pro33?3 will lead to constitutively- elevated SERT function in platelets and brain. Together, these studies represent the first opportunity to examine the presynaptic impact of ?V?3 and help elucidate pathways supporting comorbidity between mental illness and cardiovascular disease. PUBLIC HEALTH RELEVANCE: The proposed project aims to understand how integrins modulate the serotonin system using molecular and biochemical approaches. As mood disorders are associated with impaired information processing, the association between a cell adhesion receptor and the major target for antidepressant therapy reveals a novel mechanism affected by mood disorders. The protein complex studied in detail in this proposal is also a common molecular feature of mood and cardiovascular disease and provides clues to understanding the comorbidities between the two disorders.