Catalytic Antibody-Based Vaccine For Weight Loss

描述（申请人提供）：全球有近10亿人超重或肥胖（体重指数BMI分别为25-<30和bbb30 kg/m2）。虽然超重和肥胖在美国等富裕国家普遍存在，但在中国、印度和拉丁美洲等发展中国家却显著增加，构成了全球公共卫生危机。事实上，1980-2002年间，成人（20岁以上）的肥胖患病率翻了一番，儿童和青少年（6-19岁）的肥胖患病率翻了三倍。超重和肥胖通常与许多疾病有关，如心脏病、某些癌症、2型糖尿病、中风、关节炎、呼吸问题和心理障碍。因此，与肥胖相关的死亡人数已上升至每年近30万人，估计经济成本为1170亿美元。因此，开发新的治疗方法对于制止这一世界性流行病至关重要。我们研究项目的长期目标是基于最近发现的激素，胃饥饿素，开发治疗体重增加的方法，因为它具有刺激食欲和调节能量平衡的功能。我们的方法是双管齐下的，我们将开发特异性作用于胃饥饿素的催化抗体，同时我们将设计负责胃饥饿素独特的翻译后修饰的酶的抑制剂。为了实现这一目标，我们将追求以下目标：(1)我们将设计和化学合成过渡态类似物（半抗原）来水解饥饿素的正辛烷侧链。(2)我们将利用合成的半抗原免疫小鼠产生单克隆抗体。(3)我们将对每个催化抗体的动力学效率进行表征。(4)与催化抗体方法并行，我们还将使用过渡态理论来设计胃饥饿素o -酰基转移酶的抑制剂，胃饥饿素o -酰基转移酶是负责连接胃饥饿素正辛烷基侧链的酶。公共卫生相关性：超重和肥胖（体重指数，BMI，分别= 25-<30和bbb30 kg/m2）是全球流行病，影响全世界近10亿人。正因为如此，人们投入了大量的精力来发现治疗这些疾病的新方法，包括手术和非手术；然而，这些治疗往往只是治标不治本，只有在继续治疗时才有效。我们建议通过靶向一种已知在节食后增加的蛋白质来开发治疗体重增加的方法，这种蛋白质可能与随后经常观察到的体重反弹有关，这将改变肥胖治疗的范式。

DESCRIPTION (provided by applicant): Nearly 1 billion people worldwide are overweight or obese (body mass index, BMI, = 25-<30 and >30 kg/m2, respectively). Although prevalent in affluent nations such as the United States, overweight and obesity is significantly on the rise in developing nations such as China, India and Latin America representing a global public health crisis. In fact, between 1980-2002 obesity prevalence doubled in adults (age 20+ years) and tripled in children and adolescents (age 6-19 years). Overweight and obesity are commonly linked with many diseases such as heart disease, certain cancers, type 2 diabetes, stroke, arthritis, breathing problems and psychological disorders. As a result, deaths associated with obesity have risen to nearly 300,000 per year and the estimated economic cost is $117 billion. Thus, the development of new treatments is crucial in stopping this worldwide epidemic. The long-term goal of our research program is to develop therapies for the treatment of weight gain based on the recently discovered hormone, ghrelin, due to its function in stimulating appetite and regulating energy homeostasis. Our approach is two-prong in that we will develop catalytic antibodies that specifically act on ghrelin and in parallel we will design inhibitors of the enzyme responsible for ghrelin's unique posttranslational modification. Toward this goal, we will pursue the following aims: (1) We will design and chemically synthesize transition state analogs (haptens) for the hydrolysis of ghrelin's n-octanoyl side chain. (2) We will utilize the synthesized haptens for the immunization of mice to generate monoclonal antibodies. (3) We will characterize each catalytic antibody for its kinetic efficiency. (4) In parallel with the catalytic antibody approach, we will also use transition state theory to design inhibitors of ghrelin O-acyltransferase, which is the enzyme responsible for attaching ghrelin's n-octanoyl side chain. PUBLIC HEALTH RELEVANCE: Overweight and obesity (body mass index, BMI, = 25-<30 and >30 kg/m2, respectively) are global epidemics affecting nearly 1 billion people worldwide. As such, much effort has been invested in discovering new therapies, both surgical and nonsurgical, for these disorders; however, these treatments are often only palliative and effective only while treatment is continued. We propose to develop therapies for weight gain by targeting a protein known to be increased after dieting and potentially implicated in the subsequent weight regain often observed, which will change the paradigm of obesity therapy.