Multi-modal treatment for neonatal HIE: hypothermia and dendrimer nanotherapy

自伤行为(SIB)是影响智力障碍个体的最严重的疾病之一 残疾(ID)。它的特点是对个人自己的身体产生身体伤害，导致组织 损坏[1]。SIB最常见的特征包括头部撞击、自咬、戳眼睛、自抓、 扯头发，还会自拍。虽然还没有进行明确的流行病学研究 [2]，据估计，在ID或自闭症谱系障碍(ASD)患者中，SIB的患病率为5%至32%[3-7]。 慢性SIB与医疗并发症、受限的教育、职业和社交有关 机会、居住或机构安置以及较差的长期结果[8]。在严重情况下，SIB可能 造成永久性组织损伤，在极端情况下，甚至死亡。因此，SIB经常具有毁灭性的不利影响 对儿童健康、家庭功能和生活质量的影响。 随着最近出现的单核苷酸多态性(SNP)阵列和下一代 通过测序，已经有可能确定一系列临床疾病的遗传基础。近期 研究表明，像这样的从头拷贝数变异(CNV)对ID风险有很大贡献 使用SNP阵列进行测量；从从头开始的单核苷酸变体(SNV)，例如从 父亲/母亲/孩子三人组的完整外显子组测序；以及罕见的完全(纯合子)基因敲除。我们 建议确定当SIB发生在病因不明的个体中时，基因对SIB的贡献。 假设我们将看到显著的基因对他们的临床表型的贡献，鉴于极端 他们残疾的严重程度和临床特征。因为这些案例中的绝大多数都是单纯型的(即 每个家系只有一个受影响的个体)，我们假设显性的从头开始的变异(CNV和/或 SNV)将被发现与SIB相关联。 与自我伤害有关的几种遗传综合征，如Lesch-Nyhan综合征和 Cornelia de Lange综合征，潜在的遗传机制可能是SIB的原因之一。这个 我们计划研究的患者具有非常戏剧性的临床表型，同时他们的行为被研究 作为治疗方案的一部分，很少有研究来表征遗传病的基础。 失调症。预计在自我伤害的基础上存在一些遗传异质性，但临床上 异质性与共同通路的中断可能是重要的假设是一致的。我们 建议确定与SIB相关的候选基因，这些基因可能导致基于证据的 药物治疗或其他治疗方法。

Self-injurious behavior (SIB) is among the most serious conditions affecting individuals with intellectual disability (ID). It is characterized by production of physical injury to the individual's own body, resulting in tissue damage [1]. The most common topographies of SIB include head banging, self-biting, eye poking, selfscratching, hair pulling, and self-hitting. While definitive epidemiological studies have not yet been performed [2], the prevalence of SIB is estimated at 5 to 32% of persons with ID or autism spectrum disorder (ASD) [3-7]. Chronic SIB is associated with medical complications, restricted educational, vocational, and social opportunities, residential or institutional placement and poor long-term outcome [8]. In severe cases, SIB may produce permanent tissue damage or in extreme cases, death. Thus, SIB often has devastating adverse impacts on child health, family functioning, and quality of life. With the recent emergence of both single nucleotide polymorphism (SNP) arrays and next-generation sequencing, it has become possible to determine the genetic basis of a series of clinical disorders. Recent studies suggest a substantial contribution to ID risk from de novo copy number variants (CNVs) such as those measured using SNP arrays; from de novo single nucleotide variants (SNVs) such as those identified from whole exome sequencing of father/mother/child trios; and from rare complete (homozygous) knockouts. We propose to determine genetic contributions to SIB when it occurs in individuals with unknown etiology, hypothesizing that we will see significant genetic contribution to their clinical phenotypes, given the extreme severity of their disability and clinical profile. Because the vast majority of these cases are simplex (i.e. there is only one affected individual per pedigree), we hypothesize that dominant, de novo variants (CNVs and/or SNVs) will be found to be associated with SIB. Several genetic syndromes that are associated with self-injury, such as Lesch-Nyhan Syndrome and Cornelia de Lange Syndrome, implicate underlying genetic mechanisms as a possible cause of SIB. The patients we propose to study have very dramatic clinical phenotypes, and while their behaviors are studied intensively as part of a treatment regimen, there have been few studies to characterize the genetic bases of the disorders. There is expected to be some genetic heterogeneity underlying self-injury, and yet the clinical heterogeneity is consistent with the hypothesis that the disruption of common pathways may be important. We propose to identify candidate genes associated with SIB that may potentially lead to evidence-based pharmacological treatment or other therapeutic approaches.